COPS5 Data Analysis

HGNC Gene Name: COP9 signalosome subunit 5
HGNC Gene Symbol: COPS5
Identifiers: hgnc:2240 ncbigene:10987 uniprot:Q92905
Orthologs: mgi:1349415 rgd:1310301
NDEx Network: ddf35109-cac9-11eb-9a85-0ac135e8bacf
INDRA Statements: deubiquitinations all statements
Pathway Commons: Search for COPS5
Number of Papers: 310

DepMap Analysis

The Dependency Map (DepMap) is a genome-wide pooled CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene knockout is assigned a “dependency score” on a per cell-line basis which quantifies the rate of CRISPR-Cas9 guide drop. It has been found that proteins with similar DepMap scores across cell lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can include activity in the same or parallel pathways or membership in the same protein complex or the same pathway.

We identified the strongest seven co-dependent genes (“Symbol”) for DUBs and ran GO enrichment analysis. We used Biogrid, IntAct, and Pathway Commons PPIDs, and the NURSA protein-protein interaction databases (PPIDs) to determine whether co-dependent genes interact with one another. The “Evidence” column contains the PPIDs in which the interaction appears as well as whether there is support for the association by an INDRA statement. As another approach to identify potential interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB; it has previously been observed that proteins in the same complex are frequently significantly co-expressed. The correlations and associated p-values in the CCLE proteomics dataset are provided. And, we determined whether co-dependent genes yield similar transcriptomic signatures in the Broad Institute's Connectivity Map (CMap). A CMap score > 90 is considered significantly similar.

DepMap Correlations

Symbol	Name	DepMap Correlation	Evidence	CCLE Correlation	CCLE Z-score	CCLE p-value (adj)
COPS4	COP9 signalosome subunit 4	0.315	BioGRID IntAct Pathway Commons INDRA	0.83	4.50	2.50e-94
COPS3	COP9 signalosome subunit 3	0.301	BioGRID IntAct NURSA Pathway Commons INDRA	0.80	4.29	8.82e-80
COPS8	COP9 signalosome subunit 8	0.3	BioGRID IntAct Pathway Commons INDRA	0.30	1.54	5.77e-08
COPS6	COP9 signalosome subunit 6	0.271	BioGRID IntAct Pathway Commons INDRA	0.78	4.20	2.40e-74
CAND1	cullin associated and neddylation dissociated 1	0.26	BioGRID Pathway Commons INDRA	0.45	2.41	1.24e-18
GPS1	G protein pathway suppressor 1	0.254	BioGRID IntAct Pathway Commons INDRA	0.71	3.81	6.06e-55
COPS2	COP9 signalosome subunit 2	0.242	BioGRID IntAct Pathway Commons INDRA	0.75	4.05	3.10e-66

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with COPS5using the terms from Gene Ontology and gene sets derived from theGene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier	GO Name	GO Type	p-value	p-value (adj.)	q-value
GO:0000338	protein deneddylation	Biological Process	2.27e-20	1.63e-18	8.12e-19
GO:0000715	nucleotide-excision repair, DNA damage recognition	Biological Process	1.09e-17	7.85e-16	1.95e-16
GO:0008180	COP9 signalosome	Cellular Component	2.10e-16	1.51e-14	2.51e-15
GO:0006283	transcription-coupled nucleotide-excision repair	Biological Process	1.83e-14	1.32e-12	1.64e-13
GO:0006289	nucleotide-excision repair	Biological Process	2.18e-13	1.57e-11	1.56e-12
GO:0043687	post-translational protein modification	Biological Process	8.86e-13	6.38e-11	5.28e-12
GO:0070646	protein modification by small protein removal	Biological Process	1.01e-10	7.25e-09	5.15e-10

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out COPS5 using CRISPR-Cas9.

Knockout Differential Expression

Symbol	Name	log₂-fold-change	p-value	p-value (adj.)
G0S2	G0/G1 switch 2	8.51e-01	3.08e-30	6.04e-27
MMP1	matrix metallopeptidase 1	5.54e-01	1.61e-14	1.58e-11
SERPINE1	serpin family E member 1	6.72e-01	1.51e-11	9.83e-09
ANKRD1	ankyrin repeat domain 1	5.26e-01	3.97e-11	1.95e-08
FRMD6	FERM domain containing 6	6.68e-01	1.60e-10	6.27e-08
SLCO4A1	solute carrier organic anion transporter family member 4A1	-7.51e-01	7.03e-10	2.30e-07
CXCL8	C-X-C motif chemokine ligand 8	9.63e-01	3.30e-08	9.25e-06
HMGB3	high mobility group box 3	-4.18e-01	1.28e-06	3.14e-04
PLAUR	plasminogen activator, urokinase receptor	3.84e-01	3.17e-06	6.91e-04
CXCL1	C-X-C motif chemokine ligand 1	8.17e-01	4.00e-06	7.84e-04
CSF2	colony stimulating factor 2	6.80e-01	4.51e-06	8.03e-04
NQO1	NAD(P)H quinone dehydrogenase 1	-4.03e-01	6.59e-06	1.08e-03
ALDOA	aldolase, fructose-bisphosphate A	-2.85e-01	9.84e-06	1.48e-03
NOP16	NOP16 nucleolar protein	3.96e-01	1.79e-05	2.50e-03
PTX3	pentraxin 3	5.18e-01	3.52e-05	4.60e-03
CCNB1	cyclin B1	-3.25e-01	5.54e-05	6.79e-03
YY1	YY1 transcription factor	4.28e-01	7.08e-05	8.17e-03
PDRG1	p53 and DNA damage regulated 1	5.16e-01	8.53e-05	9.29e-03
LIMCH1	LIM and calponin homology domains 1	5.08e-01	9.07e-05	9.36e-03
DNTTIP2	deoxynucleotidyltransferase terminal interacting protein 2	3.80e-01	1.23e-04	1.15e-02
GNL2	G protein nucleolar 2	4.32e-01	1.19e-04	1.15e-02
SRGN	serglycin	4.33e-01	1.51e-04	1.35e-02
NUCKS1	nuclear casein kinase and cyclin dependent kinase substrate 1	-3.12e-01	1.90e-04	1.62e-02
S100A2	S100 calcium binding protein A2	-5.66e-01	2.17e-04	1.77e-02
ATP1A1	ATPase Na+/K+ transporting subunit alpha 1	-4.78e-01	2.84e-04	2.17e-02
MRTO4	MRT4 homolog, ribosome maturation factor	3.29e-01	2.88e-04	2.17e-02
BTF3	basic transcription factor 3	2.42e-01	3.84e-04	2.43e-02
CCN2	cellular communication network factor 2	3.49e-01	3.62e-04	2.43e-02
FAM166A	family with sequence similarity 166 member A	-3.92e-01	3.75e-04	2.43e-02
SPINT2	serine peptidase inhibitor, Kunitz type 2	-3.18e-01	3.54e-04	2.43e-02
TGM2	transglutaminase 2	4.20e-01	3.36e-04	2.43e-02
CCT5	chaperonin containing TCP1 subunit 5	2.35e-01	4.34e-04	2.50e-02
PTRH2	peptidyl-tRNA hydrolase 2	3.55e-01	4.13e-04	2.50e-02
VIM	vimentin	-3.39e-01	4.23e-04	2.50e-02
MT-ND2	mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 2	2.14e-01	4.60e-04	2.58e-02
ILF3	interleukin enhancer binding factor 3	3.70e-01	5.52e-04	3.01e-02
MRPS24	mitochondrial ribosomal protein S24	3.92e-01	6.03e-04	3.20e-02
PPP1R14B	protein phosphatase 1 regulatory inhibitor subunit 14B	-3.39e-01	6.43e-04	3.32e-02
BIRC5	baculoviral IAP repeat containing 5	-2.67e-01	6.95e-04	3.49e-02
GTPBP4	GTP binding protein 4	3.20e-01	7.53e-04	3.69e-02
TP53	tumor protein p53	-4.72e-01	8.43e-04	4.03e-02
MT-CO1	mitochondrially encoded cytochrome c oxidase I	3.33e-01	9.01e-04	4.21e-02
DAP3	death associated protein 3	3.71e-01	9.39e-04	4.28e-02
PLAU	plasminogen activator, urokinase	3.34e-01	1.05e-03	4.58e-02
PSMB5	proteasome 20S subunit beta 5	2.53e-01	1.04e-03	4.58e-02
JMJD1C	jumonji domain containing 1C	4.69e-01	1.13e-03	4.80e-02
TPR	translocated promoter region, nuclear basket protein	4.31e-01	1.15e-03	4.81e-02
GPATCH4	G-patch domain containing 4	3.40e-01	1.26e-03	4.82e-02
MDH1	malate dehydrogenase 1	-2.80e-01	1.26e-03	4.82e-02
MRPL14	mitochondrial ribosomal protein L14	2.39e-01	1.27e-03	4.82e-02
TIMM13	translocase of inner mitochondrial membrane 13	3.44e-01	1.19e-03	4.82e-02
VDAC1	voltage dependent anion channel 1	2.29e-01	1.28e-03	4.82e-02

INDRA Statements

Deubiquitinase Activity

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach

COPS5 deubiquitinates CD274. 8 / 8

| 8

➶

reach

Although PD-L1 had notable basal ubiquitination, CSN5 abolished ubiquitination of PD-L1 (XREF_FIG).

27866850

➶

reach

However, our results suggested that CSN5 directly deubiquitinates and stabilizes PD-L1 in cancer cells to escape from immune surveillance.

27866850

➶

reach

CSN5 in turn, prevents the ubiquitination of PD-L1, hinders its degradation and as a result enhances tumor escape from immunosurveillance.

29765155

➶

reach

Jab1 and COPS5 reduces PD-L1 ubiquitination and stabilizes it.

29535627

➶

reach

Deubiquitination and Stabilization of PD-L1 by CSN5.

27866850

➶

reach

Next we asked whether CSN5 deubiquitinates PD-L1 to increase protein stabilization.

27866850

➶

reach

Moreover, CSN5 modulated the deubiquitination and stability of PD-L1.

31802034

➶

reach

Aside from inhibiting ubiquitination, CSN5 further deubiquitinates PD-L1 directly.

27866850

UCHL3 deubiquitinates COPS5. 4 / 4

| 4

➶

reach

Given that UCHL3 interacts with COPS5 in IFN signaling and UCHL3 is a deubiquitinase, we question whether UCHL3 promotes COPS5 deubiquitination.

28583475

➶

reach

To address this question, we firstly performed an in vitro deubiquitination assay, which clearly demonstrated that UCHL3 can deubiquitinate COPS5 in vitro.

28583475

➶

reach

These results imply that UCHL3 physically interacts with COPS5 and deubiquitinates COPS5.Given that UCHL3 can deubiquitinate COPS5, we speculate that UCHL3 could affect cellular levels of COPS5.

28583475

➶

reach

Furthermore, we demonstrate that UCHL3 as a deubiquitinase can deubiquitinate COPS5, thereby upregulating COPS5 levels and protein stability (Figs. 4 and 5).

28583475

COPS5 leads to the deubiquitination of BRSK2. 3 / 3

| 3

➶

reach

We provided the evidence that Jab1 promoted the ubiquitination and degradation of BRSK2.

22609399

➶

reach

Moreover, Jab1 promotes polyubiquitination and degradation of BRSK2.

22609399

➶

reach

Intriguingly, Jab1 promoted the ubiquitination and proteasome dependent degradation of BRSK2.

22609399

COPS5 deubiquitinates PEA15. 2 / 2

| 1 1

➶

trips

Here, we report that in response to DNA damage, COPS5 deubiquitinates and stabilizes PEA15 in an ATM kinase-dependent manner.

24710276

➶

reach

Here, we report that in response to DNA damage, COPS5 deubiquitinates and stabilizes PEA15 in an ATM kinase dependent manner.

24710276

TNF leads to the deubiquitination of COPS5. 2 / 2

| 2

➶

reach

Not only epidermal growth factor (EGF)-mediated glycosylation, which could inactivate GSK3beta, but also COP9 signalosome 5 (CSN5)-mediated deubiquitination induced by TNF-alpha, stabilized PD-L1 expression on tumor cells [XREF_BIBR, XREF_BIBR, XREF_BIBR].

| 1

➶

reach

The protein CSN5, a part of the COP9 signalosome and a regulator of cell cycle proteins such as p27, has been shown to increase p53 proteasomal degradation by promoting p53 nuclear export and decreasing MDM2 auto-ubiquitination and degradation XREF_BIBR.

23885265

| 1

➶

reach

23885265

COPS5 leads to the deubiquitination of SMAD4. 1 / 1

| 1

➶

reach

Binding of Jab1 induces the ubiquitination and degradation of Smad4.

22335355

Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach

COPS5 affects CDKN1B

3 1 | 41

COPS5 decreases the amount of CDKN1B.

3 1 | 11

COPS5 decreases the amount of CDKN1B. 10 / 10

3 1 | 6

➶

trrust

No evidence text available

16951171

➶

reach

Jab1 is known to downregulate the expression of the cell cycle inhibitor p27 Kip1 in some cancer models.

30203426

➶

bel

Jab1 was also identified as a direct negative regulator of the CDK inhibitor, p27Kip1, resulting in cell cycle progression (Tomoda et al., 1999).

15480426

➶

reach

Jab1 and COPS5 negatively regulates p27 expression by exporting p27 from the nucleus to the cytoplasm, mediating p27 degradation via the proteasome pathway and promoting cell-cycle progression.

29535627

➶

reach

Thus, disruption of the Jab1 gene not only abolished JAB1 expression but also increased p27, p53 and c-Myc levels and cell death, suggesting that JAB1 is involved in maintaining the integrity and stability of critical regulators of cell proliferation and apoptosis.

20802511

➶

bel

Jun activation domain-binding protein 1 (Jab1) was originally identified as a coactivator of activator protein 1 (AP1) transcription and was also shown to promote degradation of the cyclin-dependent kinase inhibitor, p27Kip1.

15480426

➶

reach

Based on these results, we suggest that XLGalpha olf and CSN5 down-regulate the expression of p27 Kip1 cooperatively and this function is controlled by phosphorylation.Furthermore, Galpha s, classifie[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

22120635

➶

bel

Jab1 promotes degradation of the cyclin-dependent kinase inhibitor p27(Kip1)

15353483

➶

reach

Recently, Jab1 and CSN5, the fifth component of the COP9 signalosome complex, was found to specifically translocate p27Kip1 from the nucleus to the cytoplasm, and reduce the protein level of p27Kip1 by accelerating its degradation.

14719054

➶

reach

In addition, Jab1 silencing by siRNA increased p27 expression levels.

30282449

Modified COPS5 decreases the amount of CDKN1B. 5 / 5

| 5

➶

reach

Loss of Jab1 increases p27 levels in Schwann cells, which causes defective cell cycle progression and aberrant differentiation.

24344238

➶

reach

To investigate whether Jab1 overexpression in NPC cells downregulates p27 levels, we transduced those two cell lines with Jab1 adenovirus in the absence or presence of doxycycline and measured Myc-JAB and p27 levels 48 hours after infection.

22350412

➶

reach

Our findings suggest that Jab1 expression is inversely correlated with p27 expression levels, suggesting that Jab1 overexpression contributes to pathogenesis of OSCC by degradating p27 expression.

22311264

➶

reach

In breast cancer, hepatocellular carcinoma, and pancreatic adenocarcinoma, JAB1 is a negative regulator of p27, and high JAB1 expression is associated with poor prognosis and decreased p27 expression.

24604556

➶

reach

Fig. 3 shows that as previously reported, over-expression of Jab1 decreased p27 expression.

16300740

COPS5 inhibits CDKN1B.

| 13

COPS5 inhibits CDKN1B. 10 / 10

| 10

➶

reach

Overexpression of JAB1 is found to reduce the half-life of p27Kip1 from more than 5 h to 1.4 h [34], and increase the degradation rate of rLHR by 3 fold [45].

23583719

➶

reach

Jab1 promotes p27 degradation through proteolysis and is sensitive to proteasome inhibitors.

22350412

➶

reach

BRSK1 is a novel tumor suppressor in breast cancer which inversely correlated with Jab1 expression, may involve in the restoring Jab1 induced suppression of p27 (Kip1) and may regulate cell cycle through the PI3K and Akt pathway.

25036402

➶

reach

One mechanism may involve JAB1 mediated p27 KIP1 degradation [73].

24503238

➶

reach

Jab1 and CSN5 negatively regulates p27 and plays a role in the pathogenesis of nasopharyngeal carcinoma.

22350412

➶

reach

Mechanistically, Jab1 and p27 were found to interact directly in NPC cells, with Jab1 mediating p27 degradation in a proteasome dependent manner.

22350412

➶

reach

We confirmed that Jab1 over-expression induces the nuclear to cytoplasm translocation of p27 but, to our surprise, treating cells with a p8 siRNA blocked that effect almost completely, indicating that[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

16300740

➶

reach

In this study, we identified the role of Jab1 mediated p27 degradation in NPC oncogenesis.

22350412

➶

reach

Recent studies have demonstrated that jab1 contributes to carcinoma progression by degrading p27 and Kip1 protein.

12860294

➶

reach

Together, our findings suggest that Jab1 overexpression plays an important role in the pathogenesis of NPC through Jab1 mediated p27 degradation.

22350412

COPS5 bound to GFER inhibits CDKN1B. 1 / 1

| 1

➶

reach

Gfer binds to Jab1 and inhibits its destabilization of p27 kip1.

21346186

COPS5 bound to CDKN1B inhibits CDKN1B. 1 / 1

| 1

➶

reach

Because Jab1 and CSN5 directly interacts with p27 and promotes p27 degradation in the cytoplasm, Jab1 and CSN5 promotes cell cycle progression [24].

24949832

Modified COPS5 inhibits CDKN1B. 1 / 1

| 1

➶

reach

Although JAB1 translocates to the cytoplasm to increase the degradation of p27, it functions also as a transcriptional cofactor for AP-1.

12559756

COPS5 activates CDKN1B.

| 12

COPS5 activates CDKN1B. 10 / 10

| 10

➶

reach

Ectopic expression of Jab1 and CSN5 induces specific down-regulation of the cyclin dependent kinase (Cdk) inhibitor p27 (p27 (Kip1)) in a manner dependent upon transportation from the nucleus to the cytoplasm.

11278754

➶

reach

Interestingly, JAB1 mediated p27 degradation was not impaired when S-phase kinase interacting protein 2 (Skp2), an F-box protein required for the ubiquitination and consequent degradation of p27, was silenced.

16951171

➶

reach

RT-PCR method was adopted to examine the mRNA expression of the Jab1 and p27kip1 gene in Hep-2 cells which was treated with Jab1 siRNA II.

22675932

➶

reach

By inhibiting Jun activation domain binding protein 1 (Jab1) trastuzumab increases nuclear retention of p27Kip1.

15611642

➶

reach

XREF_BIBR CAPER typically interacts with ESR1 and ESR2 to work as a coactivator of transcription, while JAB1 stimulates the breakdown of the cyclin dependent kinase inhibitor p27Kip1 and regulates HIF by cleaving ubiquitin like proteins.

22701083

➶

reach

Our data indicating a direct interaction of Gfer with Jab1 to restrict Jab1 mediated destabilization of p27 kip1 (XREF_FIG) underscores the importance of a Gfer-Jab1-p27 kip1 pathway not only in the functional maintenance of normal HSCs, but also in the prevention and/or treatment of malignancies.

21346186

➶

reach

This is Jab1 and p27 (kip1) interact with each other, Jab1 accelerate p27 (kip1) from nuclear to cytoplasm through ubiquitin and proteasome pathway.

27152307

➶

reach

Jab1 overexpression may induce p27 downregulation by nuclear export.

27703676

➶

reach

Gfer inhibits Jab1 mediated degradation of p27 kip1 to restrict proliferation of hematopoietic stem cells.

21346186

➶

reach

Although the functional relevance of these mini-complexes remain elusive, XREF_BIBR have revealed that a CSN5 containing mini-complex mediated p27 kip down-regulation in leukemia cells independently of the deneddylation activity of the CSN, suggesting that the mini-complexes may have unique cellular functions.

18706515

COPS5 bound to TSPAN1 activates CDKN1B. 1 / 1

| 1

➶

reach

So we pursued the question whether Tspan-1 interacted with some other proteins to affect the ubiquitin (Ub)-proteasome system degrading p27 or interacted with Jab1 to accelerate the transportion of p27 from nucleus to cytoplasm, and then led to accelerate the tumor cells proliferation.

20890423

COPS5 bound to UCHL1 activates CDKN1B. 1 / 1

| 1

➶

reach

Binding of UCH-L1 to JAB1 promotes the nuclear export and subsequent proteasomal degradation of the cyclin dependent kinase inhibitor p27 [XREF_BIBR], resulting in increased cell proliferation (XREF_FIG).

22811913

COPS5 increases the amount of CDKN1B.

| 5

COPS5 increases the amount of CDKN1B. 5 / 5

| 5

➶

reach

MIF-(50-65) and its variant bound to the MIF binding protein JAB1 and enhanced cellular levels of p27Kip1.

12796500

➶

reach

Furthermore, we found that downregulation of Jab1 induces the cell cycle arrest at G1 phase and upregulated the expression of p27, p53 and Bax gene.

31345154

➶

reach

Conversely, down-regulation of JAB1 by short interfering RNA substantially increased p27 expression and inhibited progression from G (1) to S phase of the cell cycle.

16951171

➶

reach

Jab1 negatively regulates expression of the cell cycle inhibitor cyclin dependent kinase inhibitor 1B (P27) through binding and targeting P27 for ubiquitination and degradation.

32456285

➶

reach

For example, SC deletion of nuclear Jun activation domain binding protein 1 (Jab1) impairs radial sorting by regulating the levels of p27Kip1, which in turn promotes SC exit from the cell cycle and differentiation.

25921593

COPS5 affects TP53

| 26

COPS5 inhibits TP53.

| 11

COPS5 inhibits TP53. 10 / 10

| 10

➶

reach

How Jab1 regulates Rad51 protein and mRNA expression is not completely understood, but it is clear that Jab1 affects the major regulator of Rad51, p53, which was detected in high levels in Jab1 -/- embryos, Jab1 deficient MEFs, and Jab1 knockdown U2OS cells in our study; furthermore, these results have been supported by several other studies that found that JAB1 contributes to the stability of Mdm2 and accelerates p53 degradation and that p53 negatively regulates Rad51 at the transcriptional level through a p53 response element.

20802511

➶

reach

As Jab1 can promote the degradation of p27 [XREF_BIBR] and p53 [XREF_BIBR], we further explored the effect of T83 on these two proteins.

23815987

➶

reach

Jab1 and CSN5 knockdown also impaired proliferation and enhanced apoptosis in these cells regardless of the genotype of the tumor suppressor p53 [XREF_BIBR].

22867945

➶

reach

These results imply that Jab1 can suppress the transcriptional activity of p53, independently of subcellular localization of p53, and possibly via direct binding.

28539160

➶

reach

However, when CSN5 siRNA was co-transfected with a p53 specific siRNA, thereby blocking CSN5 siRNA induced p53 accumulation, also diminished the inducible p62 degradation and autophagosome formation in HepG2 cells.

27626169

➶

reach

Asrij and OCIAD1 suppresses CSN5 mediated p53 degradation and maintains mouse hematopoietic stem cell quiescence.

30952670

➶

reach

CSN5 can sequester p53 at the cytoplasm by either directly binding to promote the protein into the ubiquitin-proteasome-mediated protein degradation, or by linking the protein to the COP9 complex [XREF_BIBR, XREF_BIBR].

27626169

➶

reach

JAB1 also promotes the degradation of the tumor suppressor, p53, and the cyclin dependent kinase inhibitor, p27.

28366190

➶

reach

Jab1, a co-activator of AP-1 transcription factor and the fifth subunit of the COP9 signalosome, mediates degradation of the tumor suppressor p53 and p27 (Kip1) and functions as a tumor promoter in different types of human cancer.

21935931

➶

reach

As CSN5 is also known to promote the degradation of several proteins, e.g. p53, IkappaBalpha, or p27 [24,25,37], we asked if CSN5 might also affect the degradation of SIAH-1.

24882689

COPS5 inhibits mutated TP53. 1 / 1

| 1

➶

reach

Further, Jab1 could suppress the transcriptional activity of p53 mutants (XREF_SUPPLEMENTARY).

28539160

COPS5 activates TP53.

| 10

COPS5 activates TP53. 10 / 10

| 10

➶

reach

The substitution of threonine 155 for valine (T155V) abrogated Jab1 mediated p53 nuclear export, indicating that phosphorylation at this site is essential for Jab1 mediated regulation of p53.

28539160

➶

reach

We therefore used curcumin, a CSN associated kinase inhibitor, to test whether CSN dependent phosphorylation is involved in Jab1 mediated p53 regulation.

28539160

➶

reach

Curcumin prevents Jab1 mediated p53 nuclear export.

28539160

➶

reach

Jab1 induces the cytoplasmic localization and degradation of p53 in coordination with Hdm2.

16624822

➶

reach

The nuclear and cytoplasmic co-localization between COPS5 and p53 suggests a mechanism of COPS5 and p53 interaction and relocalization of p53 from the nucleus to the cytoplasm, and treatment of MG132, a potent proteasome inhibitor, significantly inhibited proteasome dependent protein degradation of p53 and enhanced its levels in cytoplasm, which indicated the degradation of p53 induced by COPS5.

32257396

➶

reach

Phosphorylation of Thr 155 on p53 is required for Jab1 mediated p53 nuclear export.

28539160

➶

reach

Here, we show that phosphorylation at the threonine 155 residue is essential for Jab1 mediated p53 nuclear export.

28539160

➶

reach

When Jab1 was co-expressed with S149D and T150E, their nuclear export pattern was similar to wild-type p53, and was inhibited by curcumin, suggesting that S149 and T150 on p53 are dispensable for Jab1 mediated p53 translocation (XREF_FIG and XREF_SUPPLEMENTARY, panels 1-12 and 21-32).

28539160

➶

reach

Consistently, we found that p53 induced by curcumin or CSN5 RNAi was lack of obvious transcriptional activity.

27626169

➶

reach

Similarly, knockdown of UCH37 and USP14 or b-AP15 treatment rescued p53 protein, induced by COPS5 overexpression, and enhanced the activity of transfected luciferase reporter plasmids for p53, Bax, and p21 expression and protein levels of p53 downstream target genes BAX and p21.

32257396

COPS5 increases the amount of TP53.

| 3

COPS5 increases the amount of TP53. 3 / 3

| 3

➶

reach

Our results demonstrated that CSN5 down-regulation by CSN5 siRNA or curcumin triggered significant p53 protein expression in cancer cells.

27626169

➶

reach

RNA interference (RNAi) of Jab1 restored the levels of the downregulated p53 and Smad4.

30870427

➶

reach

Furthermore, we found that downregulation of Jab1 induces the cell cycle arrest at G1 phase and upregulated the expression of p27, p53 and Bax gene.

31345154

COPS5 decreases the amount of TP53.

| 2

COPS5 decreases the amount of TP53. 2 / 2

| 2

➶

reach

20802511

➶

reach

Further investigation on molecular targets revealed that silencing of Jab1 obviously increased the p53 protein level thereby promoting the transcription of ubiquitin ligase Siah1 (Seven in absentia homolog 1), which aggravates the degradation of beta-catenin.

27640199

STAT3 affects COPS5

| 25

STAT3 increases the amount of COPS5.

| 16

STAT3 increases the amount of COPS5. 10 / 10

| 10

➶

reach

Because Stat3 expression in NPC was associated with Jab1 expression, we sought to determine whether the overexpression of Stat3 could enhance Jab1 transcription in NPC cells.

27524414

➶

reach

Besides, upstream activators of Stat3, such as IL-6 and Src, also promote the activation of Jab1 and COPS5 transcription and translation through interacting with Stat3.

29535627

➶

reach

Our studies also revealed that Stat3 functions by binding to Jab1 and COPS5 promoter, promotes its activity and increases Jab1 and COPS5 transcription.

29535627

➶

reach

We further investigated whether an upstream activator of Stat3, the cytokine IL-6, could be driving increased Jab1 expression.

21689417

➶

reach

In turn, the oncogenic transcription factor STAT3 positively regulates JAB1 expression, indicative of a positive feedback loop.

29113268

➶

reach

In summary, the present study demonstrates that the Src and Stat3 and C/EBP signaling pathways positively regulate the expression of the Jab1 oncogene.

21689417

➶

reach

Our previous studies demonstrated that Stat3 [XREF_BIBR] and non coding RNAs [XREF_BIBR] contribute to overexpression of Jab1 and COPS5 in cancer, and highly expressed Jab1 and COPS5 regulates DNA damage response, which confers chemotherapy and radiotherapy resistance to tumor cells [XREF_BIBR].

29228627

➶

reach

We also identify a region whereby CCAAT and enhancer binding protein-beta (C/EBP-beta), signal transducer and activator of transcription-3 (Stat3), and GATA1 induce Jab1 transcription and identify a potential upstream oncogenic signaling molecule that may be key to the regulation of Jab1 expression in cancer.

21689417

➶

reach

Treatment with the cytokine IL-6 resulted in increased Jab1 expression that was blocked by inhibition of Stat3.

21689417

➶

reach

STAT3 knockdown reduces JAB1 promoter activity, JAB1 mRNA, and JAB1 protein expression levels.

23911788

Modified STAT3 increases the amount of COPS5. 6 / 6

| 6

➶

reach

Ectopic overexpression of Stat3 increased transcriptional activity as well as mRNA and protein levels of Jab1.

21689417

➶

reach

Because Stat3 expression in NPC was associated with Jab1 expression, we sought to determine whether the overexpression of Stat3 could enhance Jab1 transcription in NPC cells.

27524414

➶

reach

Ectopic expression of Stat3 in CNE1, CNE2, and HONE1 NPC cells increased Jab1 expression (XREF_FIG and XREF_SUPPLEMENTARY).

27524414

➶

reach

As Jab1 expression in normal mammary epithelial cells is low, we asked whether overexpression of Stat3 could enhance Jab1 transcription in these cells.

21689417

➶

reach

The present study yielded strong evidence that Stat3 overexpression mediates Jab1 overexpression in NPC oncogenesis.

27524414

➶

reach

Expression of exogenous wild type Stat3 increased Jab1 expression, whereas the dominant negative EEE/VV mutation reduced Jab1 protein levels.

21689417

STAT3 activates COPS5.

| 7

STAT3 activates COPS5. 7 / 7

| 7

➶

reach

Our findings that Stat3 positively regulates Jab1 and that Stat3 depletion sensitizes NPC cells to cisplatin suggest that assessing Stat3 and Jab1 levels in NPC patients will help predict the response of their disease to cisplatin treatment and enable the design of individualized treatment strategies for these patients.

27524414

➶

reach

Taken together, these data suggest that C/EBP-beta 2 and Stat3 bind to the Jab1 promoter to increase Jab1 promoter activities.

21689417

➶

reach

Stat3 induced Jab1 transcriptional activation and protein expression.

21689417

➶

reach

Stat3 Induced Jab1 Transcriptional Activation and Protein Expression.

27524414

➶

reach

In addition, transfecting NPC cell lines with ectopic Stat3 significantly increased both the protein and RNA levels of Jab1, and inhibition of endogenous Stat3 expression with specific short interfering RNAs (siRNAs) substantially decreased Jab1 levels and inhibited cell proliferation, indicating that Stat3 positively regulates Jab1 in NPC.

27524414

➶

reach

Second, our recent studies showed that Jab1 and CSN5 is transcriptionally activated by the Stat3 signaling pathway in breast cancer [XREF_BIBR], and in a similar case, our unpublished data seem to indicate that Stat3 positively regulates Jab1 and CSN5 in NPC.

| 13

COPS5 activates apoptotic process. 10 / 10

| 10

➶

reach

Our results show that CSN5 knockdown by small interfering (si) RNA caused a strong induction of apoptosis and inhibition of cell cycle progression in HCC cells in vitro.

21499307

➶

reach

However, there were no significant differences in apoptosis induced by control and Jab1 siRNA.

22350412

➶

reach

Flow cytometric analysis proved that pJAB1 significantly enhanced apoptosis induced by staurosporine, which at least partially depended on the activation of caspase-9 and caspase-3.

24091666

➶

reach

Significantly, inhibition of CSN associated kinase activity or knockdown of CSN5 impairs JFK promoted p53 degradation, enhances p53 dependent transcription, and promotes cell growth suppression, G (1) arrest, and apoptosis.

21127074

➶

reach

As an independent apoptotic mechanism from CSN, CSN5 can enhance apoptosis via activation of transcription factor E2F1.

25139900

➶

reach

Jab1 shRNA treated cells had higher levels of cleaved caspase-3 and gamma-H2AX after cisplatin, IR and UV exposure (XREF_FIG, Top), supporting our hypothesis that Jab1 depletion enhances genotoxic stress induced apoptosis and DNA damage.

22797071

➶

reach

Porcine JAB1 significantly enhances apoptosis induced by staurosporine.

24091666

➶

reach

Interestingly, ectopic expression of JAB1 did not significantly increase apoptosis after addition of TNFalpha, presumably because it can not fully block TNFalpha mediated NF-kappaB activation (see also XREF_FIG).

19656241

➶

reach

Taken together, the mechanism of apoptosis enhanced by JAB1 need to be studied further.

27542239

➶

reach

CSN5 deficient mouse ES cells also displayed dysfunctional proliferation and accelerated apoptosis XREF_BIBR.

21991377

COPS5 bound to E2F1 activates apoptotic process. 2 / 2

| 2

➶

reach

In addition, CSN5 specifically interacts with transcription factor E2F1 and enhances E2F1 dependent apoptosis by a mechanism that is independent of deneddylation activity [39].

18926707

➶

reach

We previously showed that the E2F1 binding partner Jab1 and CSN5 promotes E2F1 dependent induction of apoptosis but not proliferation.

21937878

COPS5 bound to COPS5 activates apoptotic process. 1 / 1

| 1

➶

reach

XREF_BIBR The proapoptotic function of the E2F1 marked box is facilitated in part through the binding of Jab1 and Csn5, which promotes E2F1 dependent apoptosis but not proliferation.

19182518

COPS5 inhibits apoptotic process.

| 10

COPS5 inhibits apoptotic process. 10 / 10

| 10

➶

reach

Loss of Jab1 sensitized cells to gamma radiation induced apoptosis and increased spontaneous DNA damage and homologous recombination defects.

22797071

➶

reach

Jab1 and CSN5 inhibits cisplatin- and radiation- induced apoptosis of NPC cells.

22867945

➶

reach

Likewise, Sang et al. have reported that inhibition of Jab1 and COPS5 promoted the apoptosis through p53 related apoptotic pathways in gastric cancer cells.

29535627

➶

reach

Mechanistic investigation revealed that CSN5i-3 inhibited Jab1 expression and increased the expression of apoptosis marker cleaved caspase3 and cell cycle related protein p27 in BT474 and SKBR3 cells.

30868895

➶

reach

Positive staining using the TUNEL assay confirmed that loss of CSN5 could induce germ cell apoptosis.

12737805

➶

reach

Our results showed that knockdown of CSN5 could inhibit proliferation and promote apoptosis of gastric cancer cells.

26048783

➶

reach

Suppression of CSN5 promotes the apoptosis of gastric cancer cells through regulating p53 related apoptotic pathways.

26048783

➶

reach

Thus, in our next experiments we determined whether loss of Jab1 promotes apoptosis of NPC cells in response to DNA damage.

22797071

➶

reach

Several targets of Jab1 and CSN5, including p27, p53, c-myc, and cyclin E, were found to be highly expressed in Jab1 and CSN5 -/- embryos, resulting in impaired proliferation and accelerated apoptosis [XREF_BIBR, XREF_BIBR].

20955608

➶

reach

However, there was no significant difference between the control and Jab1-siRNA treated groups; thus, we can not conclude that Jab1 knockdown initiates apoptosis under these conditions.

22350412

COPS5 affects cell population proliferation

| 1 2 20

COPS5 activates cell population proliferation.

| 1 1 11

COPS5 activates cell population proliferation. 10 / 10

| 1 1 8

➶

sparser

Also, Jab1 activate the c-jun gene resulted cell proliferation.

27152307

➶

reach

Overexpression of JAB1 promoted the proliferation, migration, and invasion of ESCC cells, and was significantly associated with poor prognosis of ESCC patients.

32064781

➶

reach

In line with this finding, knockdown of CSN5 and CSN4 in cultured cells can significantly reduce the rate of cellular proliferation; this proliferation defect can be fully rescued by forced expression[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

18926707

➶

reach

Interestingly, Jab1 appears to induce proliferation, as demonstrated in transfection studies using Jab1 overexpressing HCC cell lines and in siRNA experiments blocking Jab1 expression [2].

17651785

➶

reach

Our data demonstrated that Jab1 protein was a vital upstream negative modulation factor of p14ARF, and Jab1 could promote cell proliferation and tumor growth via inhibiting the expression of p14ARF in vivo and in vitro.

32458234

➶

reach

Our previous studies showed that Jab1 and COPS5 was highly expressed in breast cancer and played an essential role in the breast cancer pathogenesis, and that Jab1 knockdown significantly inhibited breast cancer cell proliferation and metastasis.

31788446

➶

reach

It suggests that strong expression of Jab1 not only represents a prognostic marker for malignant transformation but also contributes to cancer cell proliferation and survival.

22350412

➶

reach

Taken together, our results suggest that Trx may regulate cell cycle and growth through a novel modulation of Jab1 mediated proliferation signals, further indicating that Trx may have the ability to control tumor progression.

15480426

➶

eidos

Jab1 promotes cell proliferation and inactivates P27 by inducing translocation of P27 from the nucleus to the cytoplasm , which accelerates P27 degradation through the Ub-dependent proteasome pathway and promotes cell cycle progression [ 34 ] .

32456285

➶

reach

This data complements previous studies demonstrating that CSN5 loss inhibits proliferation and induces apoptosis [XREF_BIBR - XREF_BIBR].

19400951

COPS5 bound to COPS5 activates cell population proliferation. 1 / 1

| 1

➶

reach

XREF_BIBR The proapoptotic function of the E2F1 marked box is facilitated in part through the binding of Jab1 and Csn5, which promotes E2F1 dependent apoptosis but not proliferation.

19182518

COPS5 bound to TSPAN1 activates cell population proliferation. 1 / 1

| 1

➶

reach

20890423

COPS5 bound to E2F1 activates cell population proliferation. 1 / 1

| 1

➶

reach

We previously showed that the E2F1 binding partner Jab1 and CSN5 promotes E2F1 dependent induction of apoptosis but not proliferation.

21937878

COPS5 inhibits cell population proliferation.

| 1 9

COPS5 inhibits cell population proliferation. 10 / 10

| 1 9

➶

reach

In mammalian cells, knock-down of CSN3 or CSN8 in cultured cells can accelerate cell proliferation [XREF_BIBR, XREF_BIBR], whereas knock-down of CSN5 decreases cell proliferation and causes cell senescence [XREF_BIBR, XREF_BIBR].

29462139

➶

reach

Interestingly, siRNA mediated depletion of Jab1 inhibited cell proliferation and accelerated apoptotic cell death in NPC.

22350412

➶

reach

Depletion of Jab1 inhibits proliferation of pancreatic cancer cell lines.

17027978

➶

reach

Knockdown of either CSN2 or CSN5 dramatically diminished cell proliferation, followed by loss of cell viability.

19400951

➶

reach

Knockdown of CSN5 inhibits the proliferation of human tumor cells XREF_BIBR XREF_BIBR, suggesting that overexpression of CSN5 not only serves as a marker of malignant transformation, but also actually contributes to tumor cell proliferation.

23316279

➶

reach

Knockdown of Jab1 inhibits proliferation and induces apoptosis in hepatocellular carcinoma cells 22.

27157611

➶

sparser

Jab1 Silencing Inhibits Proliferation and Sensitizes to Cisplatin in Biliary Tract Cancer.

30282449

➶

reach

The results showed that downregulation of Jab1 significantly inhibited glioma cell proliferation, while overexpression of Jab1 promoted it.

27640199

➶

reach

Depletion of CSN5 suppressed cell proliferation, and induced premature senescence characterized by upregulation of senescence-associated-beta-galactosidase activity and increased expression of CDK inhibitors.

23127558

➶

reach

Knockdown of Jab1 and COPS5 results in the accumulation of p27 in cell nucleus, induces cell-cycle arrest and inhibits cell proliferation.

29535627

COPS5 affects RAD51

| 19

COPS5 activates RAD51.

| 10

COPS5 activates RAD51. 10 / 10

| 10

➶

reach

Moreover, we discovered that Jab1 positively regulated Rad51 in p53 dependent manner and that overexpression of Rad51 conferred cellular resistance to adriamycin and cisplatin in Jab1 deficient cells.

30244171

➶

reach

Furthermore, Jab1 positively regulates Rad51 in NPC, explaining why Jab1 depletion sensitizes NPC cells to cisplatin, IR and UV.

22797071

➶

reach

In this study, we used three NPC cell lines (CNE1, CNE2 and HONE1) to investigate the hypothesis that Jab1 positively regulates the DNA repair protein Rad51 and, in turn, cellular response to treatment with DNA damaging agents such as cisplatin, ionizing radiation (IR) and ultraviolet (UV) radiation.

22797071

➶

reach

Recently, we found that the aberrant activation of Jab1 overexpression is correlated with a lower survival rate in NPC patients 14 and that Jab1 positively regulates the DNA repair gene Rad51 and contributes to NPC cells ' response to radiotherapy and cisplatin 15.

27524414

➶

reach

In this study, we used three NPC cell lines (CNE1, CNE2, and HONE1) to investigate the hypothesis that Jab1 positively regulates the DNA repair protein Rad51 and, in turn, cellular response to treatment with DNA damaging agents such as cisplatin, ionizing radiation (IR) and ultraviolet (UV).

22797071

➶

reach

Recently, we found that Jab1 and Csn5 positively regulates the DNA repair gene Rad51 and contributes to radiation resistance in NPC; Therefore, we hypothesized that Jab1 and Csn5 participates in the process of recurrence after radical radiotherapy in NPC patients.

25607111

➶

reach

The current finding that Jab1 positively regulates Rad51 and contributes to the response of NPC cells to cisplatin, IR and UV suggests that assessing the Jab1 level in patients may help predict response to cisplatin and radiation treatments, allowing the design of individualized treatment strategies for patients with NPC.

22797071

➶

reach

In the current study, we investigate the hypothesis that Jab1 positively regulates the DNA repair protein Rad51 and, in turn, the cellular response of breast cancer to chemotherapy with adriamycin and cisplatin.

30244171

➶

reach

Transient knockdown of JAB1 by siRNA decreased Rad51 promoter activity in U2OS (p53 WT) cells but not in Saos-2 (p53-null) cells (XREF_FIG).

20802511

➶

reach

Jab1 and Cops5 contributes to chemoresistance in breast cancer by regulating Rad51.

30244171

COPS5 increases the amount of RAD51.

| 6

COPS5 increases the amount of RAD51. 4 / 4

| 4

➶

reach

Inhibition of Jab1 and COPS5 not only decreases Rad51 level but also impaired its activity, resulting in an increase in cell apoptosis after DNA stimulus.

29535627

➶

reach

Jab1 and CSN5 knockdown not only decreased the level of Rad51 but also affected its activity.

22867945

➶

reach

These results suggested that Jab1 knockdown causes reduction in Rad51 gene expression, leading to a decreased ability of cells to repair DNA lesions through a homologous recombination pathway.

20802511

➶

reach

Jab1 knockdown not only decreased the protein level of Rad51 but also affected its repair function, as shown on XREF_FIG, which compares a reduced Rad51 foci formation in Jab1 siRNA treated cells with the Rad51 foci in control siRNA treated cells after gamma-IR.

20802511

Modified COPS5 increases the amount of RAD51. 2 / 2

| 2

➶

reach

We demonstrated that knocking down Jab1 expression in these NPC cells sensitized them to cisplatin, IR and UV radiation, and conversely, overexpression of Jab1 contributes to cisplatin and irradiation resistance in NPC cells by positively regulating the levels of the DNA repair gene Rad51.

22797071

➶

reach

Conversely, overexpression of Jab1 and CSN5 contributed to cisplatin and radiation resistance in NPC cells by positively regulating the levels of expression of the DNA repair gene Rad51.

22867945

COPS5 decreases the amount of RAD51.

| 3

COPS5 decreases the amount of RAD51. 3 / 3

| 3

➶

reach

These results suggest that depletion of Jab1 and CSN5 reduces the expression of Rad51, leading to reduce ability of NPC cells to repair DNA lesions.

22867945

➶

reach

These results suggest that Jab1 depletion reduces the expression of Rad51, leading to a reduction in the ability of cells to repair DNA lesions and an increase in apoptosis, thus sensitizing NPC cells to cisplatin, IR and UV.

22797071

➶

reach

Furthermore, Jab1 depletion not only decreased the level of Rad51 but also affected its activity, as indicated by loss of Rad51 causing extensive chromosomal breaks, leading to apoptosis.

22797071

MIF affects COPS5

1 | 1 1 15

MIF inhibits COPS5.

| 1 1 8

MIF inhibits COPS5. 10 / 10

| 1 1 8

➶

reach

For example, MIF activates mitogen activated protein kinase signaling pathways in NIH/3T3 fibroblasts 13 and endogenous MIF inhibits Jab1 activity and antagonizes Jab1 dependent cell-cycle regulation.

11875000

➶

reach

When MIF and JAB1 are bound to each other in various intracellular sites, MIF inhibits the positive regulatory effects of JAB1 on the activity of AP-1.

28366190

➶

sparser

Because JAB1 is involved in the regulation of AP1-dependent transcription and the cell cycle, and MIF inactivates JAB1 by binding to it, the cytosolic pool of MIF appears to be engaged in an additional regulatory circle distinct from the MAPK/ERK pathway.

28208600

➶

reach

MIF would thereby inhibit Jab1 enhanced AP-1 transcriptional activity [XREF_BIBR].

19413900

➶

reach

Subsequent functional studies showed that MIF can antagonize several JAB1 and CSN5 based cellular effects.

11932196

➶

reach

MIF inhibits JAB1 activity.

14502271

➶

reach

We conclude that MIF may act broadly to negatively regulate Jab1 controlled pathways and that the MIF-Jab1 interaction may provide a molecular basis for key activities of MIF.

11089976

➶

reach

Intracellular MIF sequesters CSN5 to block AP-1 transcriptional factor activity [XREF_BIBR].

26352431

➶

reach

Jab1 has been implicated in modulating MIF signaling and conversely, it is also known that MIF abrogates Jab1 mediated degradation of p27 Kip1 [25].

17560571

➶

eidos

MIF inhibits JAB1 activity .

14502271

MIF activates COPS5.

| 6

MIF activates COPS5. 6 / 6

| 6

➶

reach

The absence of MIF in females is associated with enhanced microglial activation and increased localization of JAB1 to the mitochondria in the infarcted brain.

23376686

➶

reach

At low concentrations MIF induces the release of TNF-alpha, IL-12, IL-1beta, and PGE 2 and, in a distinct difference from other " common " cytokines, involves MAPK, Akt, and PI3K activation and regulation of Jab1 and p53 [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].

22973314

➶

reach

siRNA knockdown of CSN5 and JAB1, a tumor marker and MIF binding protein, showed that JAB1 controls autocrine MIF mediated Akt signaling by inhibition of MIF secretion.

17310986

➶

reach

MIF can modulate the activator protein-1 (AP-1) pathway and cell cycle progression through interaction with the coactivator and COP9 signalosome (CSN) component JAB1 and CSN5 [20].

16122907

➶

reach

Interestingly, MIF was shown to modulate CSN5 function and subsequent CSN5 dependent effects on p27 degradation, JNK activation and AP-1-mediated transcription.

| 10

ERBB2 increases the amount of COPS5. 9 / 9

| 9

➶

reach

In this study, we reported that expression of Jab1 was stimulated by HER-2 and neu oncogene via transcriptional activation.

17914096

➶

reach

Similarly, HER-2 and neu was found to activate Jab1 and CSN5 expression through the AKT and bet-catenin pathway [XREF_BIBR].

20955608

➶

reach

Inhibition of HER-2 and neu activity by Herceptin or AG825 significantly attenuated Jab1 expression in HER-2 and neu-overexpressing MDA-MB-453 cells.

18246048

➶

reach

In addition, ErbB2 has been reported to transcriptionally activate expression of the Wnt pathway target gene Jab1 via an Akt and beta-catenin pathway in breast cancer cells.

23576562

➶

reach

HER-2 and neu transcriptionally activates Jab1 expression via the AKT and beta-catenin pathway in breast cancer cells.

17914096

➶

reach

Taken together, our results suggest that HER-2 and neu transcriptionally activates Jab1 expression to promote proliferation of breast cancer cells.

17914096

➶

reach

The regulation of Jab1 expression by HER2 through the AKT pathway is of great interest, and further studies could strengthen our understanding on the role of Jab1 in the tumorigenic process.

21689417

➶

reach

We also demonstrated that HER-2 and neu increased beta-catenin and TCF-mediated Jab1 expression via the AKT signaling pathway because chemical inhibitor or dominant negative mutant of AKT effectively attenuated the stimulatory action of HER-2 and neu.

17914096

➶

reach

HER-2 enhances Jab1 and COPS5 promoter activity and increases Jab1 and COPS5 expression through AKT and beta-catenin pathway.

29535627

Modified ERBB2 increases the amount of COPS5. 1 / 1

| 1

➶

reach

On the contrary, ectopic expression of HER-2 and neu stimulated Jab1 expression in MCF-7 cells.

18246048

ERBB2 activates COPS5.

| 4

ERBB2 activates COPS5. 4 / 4

| 4

➶

reach

In contrast to our data and other interaction effects, these studies concluded that Her2 mediated Jab1 regulation occurs at the transcriptional level.

18534028

➶

reach

Promoter activity assay suggested that HER-2 and neu oncogene upregulated Jab1 via transcriptional activation.

18246048

➶

reach

HER2 has been found to stimulate Jab1 transcriptional activity in NIH3T3 cells stably expressing the HER2 receptor [XREF_BIBR].

21689417

➶

reach

Also, HER-2 and neu activity causes mislocation of p27 and Jun activation domain binding protein 1 (JAB1), an exporter of p27, into the cytoplasm, thereby facilitating p27 degradation.

10859299

ERBB2 inhibits COPS5.

| 1

ERBB2 inhibits COPS5. 1 / 1

| 1

➶

reach

Promoter deletion and mutation analysis indicated that HER-2 and neu stimulated Jab1 via the T cell factor (TCF) binding site located at the -380/-368 region of the human Jab1 promoter.

17914096

COPS5 affects transcription, DNA-templated

| 15

COPS5 activates transcription, DNA-templated. 10 / 10

| 10

➶

reach

We show that JAB1 binds directly to the HLH domain of HAND2 and increases HAND2 transcription stimulating activity.

15139020

➶

reach

Moreover, CSN subunits may act as monomers, and CSN5 can positively regulate several transcription factors, including NFkappaB, JUN/AP-1, Hif1alpha, and E2F1.

24196835

➶

reach

21127074

➶

reach

CSN5, the fifth CSN subunit, was initially identified as c-Jun-activation-domain binding protein-1 (Jab1) that mediates AP-1-dependent gene transcription via stabilization of c-Jun [4,5].

28229932

➶

reach

As mentioned above, CSN5 was discovered as c-Jun-activation-domain binding protein JAB1, mediating AP-1-dependent gene transcription by stabilization of c-Jun [4,5].

28229932

➶

reach

Human JAB1 (Jun activation domain binding protein 1) was first described as a coactivator of c-Jun and Jun D. JAB1 enhances the ability of c-Jun and Jun D to activate transcription by stabilizing comp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

10721695

➶

reach

This includes defining mechanisms whereby LFA-1 engagement enhances transcriptional activation of numerous genes by regulating its association with transcription modulators such as JAB-1, and through interaction with other gene activating signaling complexes such as JAK-STATs.

12234372

➶

reach

Moreover, CSN5 silencing inhibited the secretion of TGF-beta, IL-1beta and IL-6 and the transcriptional activity of transcription factor NF-kappaB and Twist in human colorectal cancer cells.

26045788

➶

reach

JAB1 associates with beta2 integrins in lymphocytes and, upon alpha L beta 2 engagement, translocates into the nucleus and enhances c-Jun-driven transcription [2].

12527355

➶

reach

CSN5 enhances AP-1-mediated transcriptional activation by stabilizing complexes of the transcription factors c-Jun or JunD [9].

22120635

COPS5 bound to JUN activates transcription, DNA-templated. 2 / 2

| 2

➶

reach

Furthermore, JAB1, a transcriptional coactivator that increases the specificity of AP-1 transcription factors, interacts with both c-Jun and JunD to potentiate transcription (Claret et al., 1996).

9602173

➶

reach

The Jun activation-domain binding protein 1 (Jab1) is initially identified as a coactivator of activator protein (AP-1) transcription factor and found a component of the COP9 signalosome (CSN) complex, contained modulating signal transduction, gene transcription, and protein stability.

27152307

COPS5 bound to KMT2D activates transcription, DNA-templated. 1 / 1

| 1

➶

reach

Intracellularly, ALR binds to Jun Activation domain Binding protein 1 (JAB 1) and potentiates Activator Protein-1 (AP-1) transcription activation pathway utilizing its sulfhydryl oxidase activity XREF_BIBR, XREF_BIBR.

22292055

COPS5 bound to TGFB activates transcription, DNA-templated. 1 / 1

| 1

➶

reach

Jab1 and COPS5 directly binds to Smad4 and degrades it through the proteasome pathway and thus attenuate TGF-beta mediated gene transcription, whereas its degradation of Smad7 results in enhanced TGF-beta signaling effects.

29535627

COPS5 bound to JUND activates transcription, DNA-templated. 1 / 1

| 1

➶

reach

Furthermore, JAB1, a transcriptional coactivator that increases the specificity of AP-1 transcription factors, interacts with both c-Jun and JunD to potentiate transcription (Claret et al., 1996).

9602173

COPS5 affects BMP

| 14

COPS5 activates BMP.

| 7

COPS5 activates BMP. 7 / 7

| 7

➶

reach

Thus, aberrant accumulation of Jab1 resulting from inactivation of the CUL4B E3 ligase may enhance BMP signaling by decreasing levels of the inhibitor Smad7.For the structural basis, Jab1 ubiquitinati[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

23357576

➶

reach

Jab1 likely promotes Sox9 and BMP signaling activity during early limb development.

24604556

➶

reach

As shown in XREF_FIG, Panels A and B, we observed a reduced level of Jab1 protein and an elevated level of BMP induced alkaline phosphatase mRNA, respectively, in C2C12 cells treated with Jab1 siRNA.

24078030

➶

reach

And the upregulation of BMP signaling in response to CUL4B silencing could be partially rescued by co-depletion of Jab1, thus restoring BMP signaling to a level not significantly different from that o[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

23357576

➶

reach

Together, these data establish Jab1 as an ubiquitination target for the CUL4B ubiquitin ligase complex.In addition to its role in deneddylation [32,33], Jab1 and CSN5 has been shown to bind to Smad7, [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

23357576

➶

reach

Consistent with the results shown in Fig. 1 A and B, the transfection of pFLAG-CUL4B could almost completely rescue the BMP signaling in RNAi mediated CUL4B depletion cells, whereas FLAG-CUL4A or FLAG[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

23357576

➶

reach

These observations suggest that Jab1 may promote BMP signaling in OPCs during early limb development.

24604556

COPS5 inhibits BMP.

| 7

COPS5 inhibits BMP. 6 / 6

| 6

➶

reach

Together, our study demonstrates that Jab1 represses chondrocyte hypertrophy in vivo, likely in part by downregulating BMP signaling and Runx2 activity.

23203803

➶

reach

Furthermore, Jab1 represses chondrocyte hypertrophy in vivo, likely in part by down-regulating BMP signaling.

24604556

➶

reach

By degrading Smad4 or Smad7, Jab1 can repress or increase TGF-beta and BMP signaling, respectively, in vitro.

24604556

➶

reach

Jab1 cKO limb bud cells had significantly decreased BMP reporter activity compared with wild-type littermate controls (XREF_FIG).

24604556

➶

reach

In contrast, previously we have shown that Jab1 represses BMP signaling in differentiating chondrocytes, using a Col2a1-Cre transgene to achieve chondrocyte specific Jab1 knockout.

24604556

➶

reach

Jab1 has been reported to interact with Smad5 and cause an attenuation of BMP dependent transcriptional responses, suggesting that Jab1 might act as an inhibitor of BMP signaling XREF_BIBR.

27581523

COPS5 bound to SMAD5 inhibits BMP. 1 / 1

| 1

➶

reach

Although Jab1 can interact with the bone morphogenetic protein (BMP) downstream effector Smad5 to repress BMP signaling in vitro, the role of Jab1 in BMP mediated skeletogenesis in vivo is still poorly understood.

23203803

COPS5 affects NFkappaB

| 14

COPS5 activates NFkappaB.

| 8

COPS5 activates NFkappaB. 6 / 6

| 6

➶

reach

It has to be noted though that the effect of Csn5 and JAB1 on NF-kappaB seems to depend on the cell type and cellular context, as loss of JAB1 was also reported to reduce NF-kappaB activity, e.g. in thymocytes [XREF_BIBR] or synovial fibroblasts of rheumatoid arthritis patients [XREF_BIBR].

19656241

➶

reach

In their study, the authors found that depletion of CSN5 increased NF-kappaB activity.

28623958

➶

reach

Moreover, CSN5 silencing inhibited the secretion of TGF-beta, IL-1beta and IL-6 and the transcriptional activity of transcription factor NF-kappaB and Twist in human colorectal cancer cells.

26045788

➶

reach

However, Jab1 can activate NF-kappaB through Bcl-3 without forming a detectable complex with Bcl-3 and p50, suggesting that Jab1 transiently interacts with a complex of Bcl-3 and p50 [7].

20226764

➶

reach

Knock-down of Csn5 and JAB1 clearly enhanced basal NF-kappaB activity and improved cell survival under stress.

19656241

➶

reach

Mechanistically, Csn5 KO potentiated NF-kappaB signaling and proinflammatory cytokine expression in macrophages, whereas HIF-1alpha levels were reduced.

28292897

COPS5 bound to BCL3 activates NFkappaB. 1 / 1

| 1

➶

reach

Jab1 and CSN5 binds to Bcl-3 to enhance NF-kappaB, p50, and DNA complex formation and may link NF-kappaB and AP-1 gene transcription [XREF_BIBR].

20955608

COPS5 bound to MIF activates NFkappaB. 1 / 1

| 1

➶

reach

Consistent with its diverse functions and the large array of cell types that produce it, the downstream effects of MIF are extensive : MIF activates MAPK signaling pathways 16, promotes LPS stimulation through TLR4 17, interacts with Jab1 to increase transcription of AP-1 target genes 18, and activates NF-kappaB 19.

27049059

COPS5 inhibits NFkappaB.

| 6

COPS5 inhibits NFkappaB. 6 / 6

| 6

➶

reach

Further, siRNA mediated repression of CSN5, a subunit of the COP9 signalosome responsible for deneddylation of Cul-1, partially reversed HPC mediated inhibition of NF-kappaB.

17318263

➶

reach

Gene suppression of the CSN subunit JAB1 and Csn5 augmented constitutive NF-kappaB activity, while ectopic expression of JAB1 reduced it.

19656241

➶

reach

Furthermore, CSN5 silencing enhanced TNF-alpha-induced IkappaB-alpha degradation and NF-kappaB activity in luciferase reporter assays.

23636414

➶

reach

JAB1 silence induced Ik-Balpha degradation, enhanced NF-kappaB activity, increased the TNF-a-induced expression of adhesion molecules (CCL2, ICAM-1, VCAM-1) and induced monocytes arrest rate on inflamed endothelium in vitro [XREF_BIBR].

28173800

➶

reach

The work of others has demonstrated that CSN5 is a negative regulator of NF-kappaB and a decrease in CSN5 increases nuclear NF-kappaB thereby stimulating proliferation.

28623958

➶

reach

This notion was supported by reporter gene assays for NF-kappaB activity, which revealed that ectopic expression of JAB1 significantly reduces basal NF-kappaB activity, while suppression of endogenous JAB1 by RNA interference leads to a prominent up-regulation (XREF_FIG).

19656241

COPS5 affects JUN

1 | 1 12

COPS5 activates JUN.

1 | 1 9

COPS5 activates JUN. 10 / 10

| 1 9

➶

reach

When transfected into HeLa cells, p38 (JAB1) potentiates the transcriptional activity of c-Jun, but co-transfection with rLHR prevents this effect.

10788448

➶

reach

Overexpression of CSN5 can not rescue c-Jun destabilization in siCSN1.

18093314

➶

reach

10721695

➶

reach

10721695

➶

reach

For instance, JAB1 enhances c-Jun transactivation by enhancing binding to their cognate DNA sequences [39,40].

23583719

➶

reach

COPS5 (official gene symbol of CSN5) is responsible for the deneddylation activity of the COP9 signalosome, and also known as Jab1 to activate c-Jun (Jun-activating and binding protein).

27903243

➶

reach

CSN5 enhances AP-1-mediated transcriptional activation by stabilizing complexes of the transcription factors c-Jun or JunD [9].

22120635

➶

trips

Jab1 co-activation of c-Jun is abrogated by the serine 10-phosphorylated form of p27Kip1.

12119282

➶

reach

In addition, VDUP1 inhibited JAB1 mediated activator protein-1 activation and cell proliferation.

15930262

➶

reach

Jab1 is a coactivator of c-Jun that enhances the transcriptional function of c-Jun.

30282449

COPS5 activates JUN. 1 / 1

1 |

➶

bel

Jab1 activates c-Jun amino-terminal kinase (JNK) activity and enhances endogenous phospho-c-Jun levels, and MIF inhibits these effects. MIF also antagonizes Jab1-dependent cell-cycle regulation by increasing p27Kip1 expression through stabilization of p27Kip1 protein

11089976

COPS5 inhibits JUN.

| 2

COPS5 inhibits JUN. 2 / 2

| 2

➶

reach

In CSN5 knockdowns c-Jun destabilization was rescued by CSN5 overexpression, demonstrating the substrate receptor role of CSN5.

18093314

➶

reach

Loss-of-function studies, using Jab1 small interfering RNA, demonstrated that Jab1 knockdown blocked PAR-2-induced activator protein-1 activation.

16410250

COPS5 increases the amount of JUN.

| 1

COPS5 increases the amount of JUN. 1 / 1

| 1

➶

reach

Jab1 also stabilizes certain proteins, such as hypoxia inducible factor 1alpha and c-Jun, and potentiates c-Jun and MYC transcription, which is responsible for the transcriptional activation of genes involved in cell proliferation, angiogenesis, and invasion.

28270496

COPS5 affects COPS5

| 14

COPS5 increases the amount of COPS5.

| 6

COPS5 increases the amount of COPS5. 4 / 4

| 4

➶

reach

This suggests that pJab1 plasmid specifically targeting Jab1 gene expression could be an effective therapy for human laryngeal carcinoma.

22883584

➶

reach

To address the role of Jab1 and Sec6 in more depth, further research is needed to investigate how Jab1 modulates p27 phosphorylation at Thr157 and Sec6 regulates Jab1 expression.In a previous study, w[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

24949832

➶

reach

20802511

➶

reach

Silencing of CSN5 mRNA using siRNA decreased the endogenous protein level of CSN5 and activated L-type Ca (2+) channels expressed in COS7 cells.

16483597

Modified COPS5 increases the amount of COPS5. 2 / 2

| 2

➶

reach

Nevertheless, it appears that the obtained reductions in JAB1 levels have lowered cellular JAB1 levels below a critical threshold value that is otherwise necessary to maintain JAB1 function in positiv[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

16122907

➶

reach

Interestingly enough, in CSN8-null cells, CSN5 protein level did not diminish XREF_BIBR, consistent with the notion that full upregulation of cyclin E requires loss of CSN5, in addition to the inactivation of the CSN complex.

23316279

COPS5 inhibits COPS5.

| 3

COPS5 inhibits COPS5. 3 / 3

| 3

➶

| 10

COPS5 activates cisplatin. 10 / 10

| 10

➶

reach

Depletion of Jab1 by siRNA, which leads to inhibition of proliferation, enhanced cisplatin activity in NPC.

22350412

➶

reach

By contrast, exogenous Jab1 expression enhanced the resistance of NPC cells to cisplatin, IR and UV radiation.

22797071

➶

reach

In conclusion, we demonstrated that Jab1 contributes to the sensitivity and resistance of NPC cells to cisplatin and irradiation.

22797071

➶

reach

By contrast, exogenous Jab1 expression enhanced the resistance of breast cancer cells to adriamycin and cisplatin.

30244171

➶

reach

Moreover, Jab1 depletion enhanced the antitumor effects of cisplatin in NPC cells.

22350412

➶

reach

On the basis of our previous findings, we hypothesized that Jab1 contributes to cisplatin, IR and UV resistance.

22797071

➶

reach

By contrast, exogenous Jab1 expression enhanced the resistance of NPC cells to cisplatin, IR and UV Moreover, we provide a mechanism by which Jab1 positively regulated Rad51 through p53 dependent pathway, and increased ectopic expression of Rad51 conferred cellular resistance to cisplatin, IR and UV in Jab1 deficient cells.

22797071

➶

reach

22797071

➶

reach

27524414

➶

reach

Similarly, the levels of phospho-Chk2, a key molecule in transducing DNA damage signals, were increased after cisplatin and UV exposure regardless of whether the cells were treated with Jab1 siRNA (although the phospho-Chk2 levels were higher in Jab1 deficient cells).

22797071

COPS5 inhibits cisplatin.

| 3

COPS5 inhibits cisplatin. 3 / 3

| 3

➶

reach

In addition, Jab1 silencing potentiated the anti-proliferative and anti-migratory effects of cisplatin by increasing DNA damage.

30282449

➶

reach

We firstly tested whether inhibition of Jab1 enhances the antitumor effects of cisplatin by MTT assay.

22350412

➶

reach

In addition, Jab1 silencing potentiated the anti-proliferative effects of cisplatin.

30282449

COPS5 affects cell cycle

| 13

COPS5 activates cell cycle.

| 9

COPS5 activates cell cycle. 9 / 9

| 9

➶

reach

In contrast, Jab1 does not synergize with E2F1 to promote cell cycle entry.

16481464

➶

reach

Our group recently found that Jab1 contributes to NPC tumorigenesis and resistance to radiotherapy by promoting NPC cell growth, dysregulating NPC cell cycle progression, and inhibiting radiation induced apoptosis XREF_BIBR, XREF_BIBR, XREF_BIBR.

27157611

➶

reach

As Jab1 modulates the cell cycle in other cell types, we investigated Schwann cell number, survival, and cell cycle progression in Jab1 -/- nerves.

24344238

➶

reach

CSN5 silencing inhibits invasion and arrests cell cycle progression in human colorectal cancer SW480 and LS174T cells in vitro.

26045788

➶

reach

Because Jab1 and CSN5 directly interacts with p27 and promotes p27 degradation in the cytoplasm, Jab1 and CSN5 promotes cell cycle progression [24].

24949832

➶

reach

Jab1 (Jun activation domain binding protein 1), integrated into COP9 signalosome complex (CSN), induces protein instability of many tumor suppressors and cell cycle regulators and is therefore a novel target in cancer therapy.

19395473

➶

reach

Our results show that CSN5 knockdown by small interfering (si) RNA caused a strong induction of apoptosis and inhibition of cell cycle progression in HCC cells in vitro.

21499307

➶

reach

Dysregulation of COPS5 activity has been shown to contribute to oncogenesis through its function in cell proliferation [XREF_BIBR], cell cycle progression [XREF_BIBR], and cell chemo- and radio-resistance [XREF_BIBR, XREF_BIBR], that are mediated by the various target molecules such as MDM2, p27, HIF-1alpha, and AP-1 [XREF_BIBR].

29755680

➶

reach

We also found that knockdown of CSN5 remarkably suppressed cell growth by inducing cell cycle arrest and apoptosis promotion in NSCLC cells.

29596838

COPS5 inhibits cell cycle.

| 4

COPS5 inhibits cell cycle. 4 / 4

| 4

➶

reach

As the cellular abundance of p27 is an indicator of cell cycle, we thus reviewed relative articles to find whether the cell cycle arrest effect caused by COPS5 or COPS6 inhibition was p27 dependent.

28919423

➶

reach

CSN5 and Jab1 elimination inhibited progression of the cell cycle at multiple points, seemed to initiate p53 independent senescence and increased the ploidy of cells.

20974137

➶

reach

We found that in Schwann cells, cell cycle arrest caused by loss of COPS5 could be restored by genetic depletion of p27 [18].

28919423

➶

reach

The co-transfection of Jab1 with BRSK2 reduced cell cycle arrest at G2/M phase from 30% to 19%.

22609399

COPS5 affects AP1

| 1 2 10

COPS5 activates AP1.

| 1 2 7

COPS5 activates AP1. 10 / 10

| 1 2 7

➶

sparser

Furthermore, overexpression of hAPH2 could increase apoptosis of COS-7 cells and negatively regulate JAB1-induced activation of AP-1 in a concentration dependent manner.

17123647

➶

sparser

In this study, we found that hAPH2 could antagonize the activation of AP-1 induced by JAB1 in COS-7 cells, but we are not able to find whether this negative effect on AP-1 activity is JAB1 dependent o[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

17123647

➶

reach

Furthermore, overexpression of hAPH2 could increase apoptosis of COS-7 cells and negatively regulate JAB1 induced activation of AP-1 in a concentration dependent manner.

17123647

➶

reach

Given that hAPH2 could interact with JAB1, we further investigated whether hAPH2 could modulate JAB1 induced AP-1 activity.

17123647

➶

eidos

The binding of MIF with JAB1 / CSN5 also modulates AP-1 activity and cell proliferation by inactivation of p53 [ 8] .

32344747

➶

reach

MIF would thereby inhibit Jab1 enhanced AP-1 transcriptional activity [XREF_BIBR].

19413900

➶

reach

HPO site directed mutants (Cys and Ser) at active sites, which lost sulfhydryl oxidase activity, could not increase c-Jun phosphorylation and failed to potentiate JAB1 mediated AP-1 activation.

14500725

➶

reach

Interestingly, JAB-1 does not appear to potentiate AP-1 activity after TCR stimulation (unpublished data).

14707112

➶

reach

Furthermore, the data indicated that E9730 appeared to enhance Jab1 induced AP-1 activity in a concentration dependent manner and Jab1 may be involved in the intracellular signaling transduction from E9730 to AP-1.

14732868

➶

reach

MIF inhibits JAB1 and CSN5 mediated AP-1 activity and reduces JNK activity stimulated by JAB1 and CSN5.

11932196

COPS5 inhibits AP1.

| 3

COPS5 inhibits AP1. 3 / 3

| 3

➶

reach

As is shown in Fig. 9, group 1 that is transfected with AP-1-Luciferase and pCMV-Myc vector showed nearly no activity of the luciferase reporter, while overexpression of c-jun (group 2) and Jab1 (grou[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

17123647

➶

reach

We have demonstrated that CARP repressed JAB1 mediated AP-1 activation and enhanced p27 nuclei accumulation XREF_BIBR.

24870804

➶

reach

The cotransfection of HBx and Jab1 resulted in substantial activator protein 1 (AP-1) activation and knockdown of endogenous Jab1 attenuated AP-1 activation caused by HBx.

16247477

COPS5 affects TGFB

| 12

COPS5 activates TGFB.

| 7

COPS5 activates TGFB. 4 / 4

| 4

➶

reach

Csn5 and Jab1 can modulate TGF-beta superfamily signaling that is mediated by TGF-beta and BMP through direct interaction with various Smads.

26807424

➶

reach

It is possible that overexpression of Jab1 and CSN5 during the tumorigenic process results in enhanced TGF-beta signaling that contributes to the progression of the disease.

20955608

➶

reach

23357576

➶

reach

Moreover, CSN5 silencing inhibited the secretion of TGF-beta, IL-1beta and IL-6 and the transcriptional activity of transcription factor NF-kappaB and Twist in human colorectal cancer cells.

26045788

COPS5 bound to SMAD7 activates TGFB. 1 / 1

| 1

➶

reach

Jab1 binds to Smad4, Smad5, and Smad7, key intracellular signaling molecules of the TGF-beta superfamily, and causes ubiquiti nation and/or degradation of these Smads.

24078030

COPS5 bound to SMAD4 activates TGFB. 1 / 1

| 1

➶

reach

Jab1 binds to Smad4, Smad5, and Smad7, key intracellular signaling molecules of the TGF-beta superfamily, and causes ubiquiti nation and/or degradation of these Smads.

24078030

COPS5 bound to SMAD5 activates TGFB. 1 / 1

| 1

➶

reach

Jab1 binds to Smad4, Smad5, and Smad7, key intracellular signaling molecules of the TGF-beta superfamily, and causes ubiquiti nation and/or degradation of these Smads.

24078030

COPS5 inhibits TGFB.

| 5

COPS5 inhibits TGFB. 4 / 4

| 4

➶

reach

Our data suggest that Jab1 antagonizes TGF-beta function by inducing degradation of Smad4 through a distinct degradation pathway.

11818334

➶

reach

Jab1 antagonizes TGF-beta function by inducing uniquitin mediated degradation of Smad4.

24127404

➶

reach

By degrading Smad4 or Smad7, Jab1 can repress or increase TGF-beta and BMP signaling, respectively, in vitro.

24604556

➶

reach

Jab1 antagonizes TGF-beta signaling by inducing Smad4 degradation.

11818334

COPS5 bound to SMAD4 inhibits TGFB. 1 / 1

| 1

➶

reach

29535627

COPS5 affects NCOR

| 11

COPS5 inhibits NCOR.

| 9

COPS5 inhibits NCOR. 9 / 9

| 9

➶

reach

To further evaluate the role of COP9 complex in COPS5 mediated NCoR protein degradation, we examined the role of some COP9 subunits by RNAi.

27375289

➶

reach

However, when COPS5 is amplified and overexpressed in endocrine resistant cancer cells, elevated COPS5 and COP9 activity induces global NCoR protein degradation.

27375289

➶

reach

Low basal level of COP9 and COPS5 is associated with NCoR and constantly degrade and recycle the NCoR complex as part of the repression strategy to prevent coactivator recruitment, similar to the mechanism of cyclical activation XREF_BIBR XREF_BIBR.

27375289

➶

reach

Therefore, tamoxifen retains as an antagonist; (2) in tamoxifen resistant cells, NCoR is globally diminished by degradation due to COPS5 overexpression and consequently high levels of COP9 and COPS5 activity.

27375289

➶

reach

It is also confirmed that overexpression of Jab1 and COPS5 degrades NCoR protein through the ubiquitination-proteasome pathway in breast cancer.

29535627

➶

reach

Satisfyingly, COPS5 reduction and subsequent NCoR upregulation by COPS5 shRNA were observed at the end point of doxycycline and tamoxifen-treatment at day 42 in vivo (XREF_SUPPLEMENTARY, last two lanes).

27375289

➶

reach

Interestingly, overexpression of COPS5 induces ubiquitination and proteasomal degradation of the NCoR protein, a key corepressor of tamoxifen bound ERalpha, leading to de-repression of ERalpha target genes in resistant breast cancer (XREF_FIG, XREF_FIG, XREF_FIG, XREF_FIG).

27375289

➶

reach

However, in 4OHT resistant MCF7 cells, neither NCoR nor COP9 was recruited, whereas ERalpha and PCAF were able to bind to the promoter on 4OHT-treatment (XREF_FIG, black bars), due probably to global loss of NCoR by overexpression of COPS5.

27375289

➶

reach

Next, we noticed that NCoR protein, rather than mRNA, was downregulated by overexpression of WT COPS5 in parental MCF7 cells (XREF_FIG, XREF_SUPPLEMENTARY).

27375289

COPS5 decreases the amount of NCOR.

| 2

COPS5 decreases the amount of NCOR. 2 / 2

| 2

➶

reach

In COPS5 overexpressing tamoxifen resistant MCF7 clone # 3, RNAi mediated knockdown of GPS1 and CSN1 (two independent short hairpin RNAs (shRNAs)), CSN2 (one shRNA), COPS5 (two independent shRNAs) or CSN6 (two independent shRNAs) invariably caused induction of NCoR protein expression (XREF_FIG).

27375289

➶

reach

These data strongly suggest that loss of NCoR protein expression by COPS5 amplification and overexpression is a driver of mediating tamoxifen-resistance.

27375289

CUL4B affects COPS5

| 11

CUL4B inhibits COPS5.

| 7

CUL4B inhibits COPS5. 7 / 7

| 7

➶

reach

Omission of the ubiquitin, E1 and E2, or CUL4B immunocomplexes diminished the Jab1 polyubiquitin ladder.

23357576

➶

reach

Here, accumulation of Jab1 caused by CUL4B knockdown leads to a considerable increase in BMP signaling, which may play a mechanistic role in this process.

23357576

➶

reach

Consistent with the known function of Jab1, the current findings show that the accumulation of Jab1 caused by CUL4B knockdown also leads to a considerable upregulation in BMP signaling.XLID occurrence[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

23357576

➶

reach

Notably, CUL4B silencing did not cause a change in abundance in the three other homologous mammalian CSN proteins (CSN2, CSN4, and CSN6), indicating the specificity of CUL4B targeted Jab1 degradation.

23357576

➶

reach

CUL4B E3 ligase was shown to mediate the proteasomal degradation of Jab1.

23357576

➶

reach

Here, the experimental evidences showed that CUL4B, but not CUL4A, mediates the proteasomal degradation of Jab1.

23357576

➶

reach

Next, cells treated with siRNAs specific for CUL4B, CUL4B + Jab1 (to offset the effect of Jab1 accumulation caused by silencing of CUL4B), or with control siRNAs.

23357576

CUL4B activates COPS5.

| 3

CUL4B activates COPS5. 3 / 3

| 3

➶

reach

X linked intellectual disability gene CUL4B targets Jab1 and CSN5 for degradation and regulates bone morphogenetic protein signaling.

23357576

➶

reach

23357576

➶

reach

As expected, silencing of both CUL4B and Jab1 decreased Jab1 immunofluorescence signals and increased Smad7 signals to levels almost equal to those observed in control RNAi treated cells.

23357576

CUL4B increases the amount of COPS5.

| 1

Modified CUL4B increases the amount of COPS5. 1 / 1

| 1

➶

reach

As shown in Fig. 1 A, lane 3, expression of FLAG-CUL4B could completely rescue the levels of endogenous Jab1.

23357576

COPS5 affects SMAD4

1 | 10

COPS5 inhibits SMAD4.

1 | 5

COPS5 inhibits SMAD4. 6 / 6

1 | 5

➶

reach

Importantly, JAB1 has been observed to interact with and induce degradation of SMAD4 [51].

28923280

➶

reach

Jab1 induced Smad4 degradation results in reduced TGF-beta and BMP mediated gene transcription [XREF_BIBR].

24078030

➶

reach

Jab1 can cause degradation of Smad4 via TGF-beta signal pathway, consequently contributing to the proliferation of PC cells.

26464677

➶

signor

We report a novel mechanism of smad4 degradation. Jab1 interacts directly with smad4 and induces its ubiquitylation for degradation

11818334

➶

reach

Examination of the effects of JAB1 induced Smad4 degradation indicates that Jab1 inhibited TGF-beta-induced gene transcription.

11818334

➶

reach

Jab1 and CSN5 induced Smad4 degradation results in reduced TGF-beta-mediated gene transcription, whereas its degradation of Smad7 leads to enhanced TGF-beta signaling effects [XREF_BIBR, XREF_BIBR].

20955608

COPS5 activates SMAD4.

| 3

COPS5 activates SMAD4. 3 / 3

| 3

➶

reach

Jab1 antagonizes TGF-beta signaling by inducing Smad4 degradation.

11818334

➶

reach

By degrading Smad4 or Smad7, Jab1 can repress or increase TGF-beta and BMP signaling, respectively, in vitro.

| 7

COPS5 inhibits CUL1. 4 / 4

| 4

➶

reach

Since the neddylated : non neddylated Cul1 ratio is higher than normal in csn5 null mutants and lower than normal in Int6 mutants, we reasoned that the csn5 null mutation should rescue the reduced Cul1 neddylation in Int6 mutants.

18493598

➶

reach

Interestingly, we noticed that COPS5 recently was reported to inhibit Cullin1 neddylation (Cope et al., 2002; Muromoto et al., 2013).

28583475

➶

reach

Importantly, JAB1 knockdown induced the activation of SCF ubiquitin ligase complex containing Cullin 1 (CUL1), as judged by the enhancement of covalent modification of CUL1 with the ubiquitin like protein NEDD8, and markedly reduced the basal protein level of IFNR.

24043623

➶

reach

siRNA mediated CSN5 silencing was sufficient to disrupt the CSN complex, and induced Cullin 1 hyperneddylation which was paralleled by a decrease in free NEDD8 (XREF_FIG).

21499307

COPS5-H127A inhibits CUL1. 1 / 1

| 1

➶

reach

In contrast, expression of mutant CSN-5 (H127A, H129A, or D140N) failed to decrease the hyperneddylated Cul1 in the csn-5 KO strain (XREF_FIG).

22589747

COPS5-H129A inhibits CUL1. 1 / 1

| 1

➶

reach

In contrast, expression of mutant CSN-5 (H127A, H129A, or D140N) failed to decrease the hyperneddylated Cul1 in the csn-5 KO strain (XREF_FIG).

22589747

COPS5-D140N inhibits CUL1. 1 / 1

| 1

➶

reach

In contrast, expression of mutant CSN-5 (H127A, H129A, or D140N) failed to decrease the hyperneddylated Cul1 in the csn-5 KO strain (XREF_FIG).

22589747

COPS5 activates CUL1.

| 4

COPS5 activates CUL1. 4 / 4

| 4

➶

reach

The perdurance of the pre-recombinant wild type CSN5 or Nedd8 proteins in post-recombinant mosaic clones for CSN5 or Nedd8 mutations in some cases could allow neurons to successfully execute the Cullin1 mediated earlier program and pass the presumable threshold.

19855832

➶

reach

Subsequently, UCHL3 mediated upregulation of COPS5 promotes Cullin1 deneddylation.

28583475

➶

reach

Here we show that MsrA interacts with Jab1 and consequently, the Jab1 deneddylase activity (removal of Nedd8) is enhanced, causing an increased deneddylation of Cul-1.

32456285

➶

reach

We found these CSN6 mutants compromised their competitive activity in preventing binding between CSN5 and Cullin-1 when compared with wt CSN6; therefore, their capacity to interfere with endogenous CSN5 mediated deneddylation of Cullin-1 was also altered (XREF_FIG).

25395170

COPS5 affects SMAD7

1 | 9

COPS5 inhibits SMAD7.

| 6

COPS5 inhibits SMAD7. 6 / 6

| 6

➶

reach

Jab1, as a component of Smurf 1/2 E3 ligases, promotes Smad7 degradation [34], serving to negatively regulate BMP signaling by interfering with the phosphorylation of R-Smads [42,43].

23357576

➶

reach

23357576

➶

reach

However, Jab1 was also shown to interact with and induce the degradation of Smad7, resulting in increased TGF-beta signaling [XREF_BIBR].

27418125

➶

reach

For example, TIEG and Foxp3 enhance TGF-beta signaling through the repression of Smad7 gene expression, AMSH and AMSH2 interact with inhibitory Smads and suppress their effects, and Jab1 and CSN5 induce Smad7 degradation.

21795712

➶

reach

As expected, silencing of both CUL4B and Jab1 decreased Jab1 immunofluorescence signals and increased Smad7 signals to levels almost equal to those observed in control RNAi treated cells.

23357576

➶

reach

The Smad7 transcriptional regulation is mediated by the Ski protein, which inhibits the Smad7 promoter, and the posttransductional regulation is mediated through the effects of Smurf and Jab1 proteins, which promote Smad7 degradation [XREF_BIBR, XREF_BIBR].

19878580

COPS5 activates SMAD7.

| 2

COPS5 activates SMAD7. 2 / 2

| 2

➶

reach

Here we report that Jab1 and CSN5, which is a component of the COP9 signalosome complex, associates constitutively with Smad7 and that overexpression of Jab1 and CSN5 causes the translocation of Smad7 from the nucleus to the cytoplasm, promoting its degradation.

14993265

➶

reach

By degrading Smad4 or Smad7, Jab1 can repress or increase TGF-beta and BMP signaling, respectively, in vitro.

24604556

COPS5 decreases the amount of SMAD7.

1 | 1

Modified COPS5 decreases the amount of SMAD7. 1 / 1

| 1

➶

reach

The inhibition of endogenous Jab1 and CSN5 expression by small interfering RNA (siRNA) induces Smad7 expression.

14993265

COPS5 decreases the amount of SMAD7. 1 / 1

1 |

➶

bel

Here we report that Jab1/CSN5, which is a component of the COP9 signalosome complex, associates constitutively with Smad7 and that overexpression of Jab1/CSN5 causes the translocation of Smad7 from the nucleus to the cytoplasm, promoting its degradation

14993265

COPS5 affects Neoplasm Metastasis

| 1 8

COPS5 activates Neoplasm Metastasis. 9 / 9

| 1 8

➶

eidos

Our previous studies showed that Jab1 / COPS5 was highly expressed in breast cancer and played an essential role in the breast cancer pathogenesis , and that Jab1 knockdown significantly inhibited breast cancer cell proliferation and metastasis ( 12 ) .

31788446

➶

reach

Additionally, CSN5 contributes to the metastasis and EMT (epithelial-mesenchymal transition) of RCC cells.

28479251

➶

reach

CSN5 promotes the invasion and metastasis of pancreatic cancer by stabilization of FOXM1.

30352219

➶

reach

Moreover, the anti-metastasis role of CSN5 silence was reversed by MMP2 overexpression, whereas knockdown of MMP2 decreased PC metastasis driven by upregulation of CSN5.

30352219

➶

reach

Taken together, the results indicate that CSN5 can contribute to PC invasion and metastasis through activation of FOXM1 and MMP2 axis.

30352219

➶

reach

31788446

➶

reach

Further investigation revealed that CSN5 led to the metastasis and EMT activation of RCC cells through increasing ZEB1 expression.

28479251

➶

reach

Further, silencing of CSN5 expression markedly inhibited PC invasion and metastasis in vitro and in vivo, accompanied by decreased MMP2 expression.

30352219

➶

reach

CSN5 promotes renal cell carcinoma metastasis and EMT by inhibiting ZEB1 degradation.

28479251

Curcumin affects COPS5

| 9

Curcumin inhibits COPS5.

| 8

Curcumin inhibits COPS5. 8 / 8

| 8

➶

reach

Curcumin treatment triggered CSN5 degradation, p53 accumulation, and p62 down-regulation concomitantly at 6 h in HCT116 wt and HT29 cells, respectively, but the same CSN5 down-regulation failed to alter p62 in p53-null HCT116 p53-/- cells.

27626169

➶

reach

Second, curcumin inhibits CSN5 associated kinase activity and, therefore, curcumin can inhibit pre-existing CSN5 activity in cancer cells as it can significantly reduce 4T1 tumor growth under natural conditions.

27866850

➶

reach

Curcumin, which has been shown to inhibit CSN5 associated kinase activity, inhibited not only CSN5 activity in a dose dependent manner in vitro (XREF_SUPPLEMENTARY) but also TNF-alpha-induced PD-L1 stabilization in cells from different types of cancers, including breast, colon, and lung cancer, and melanoma (XREF_FIG and XREF_SUPPLEMENTARY).

27866850

➶

reach

Taken together, we propose that CSN5 down-regulation by curcumin is responsible for giving rise to a rapid p53 protein accumulation without significant activation of intrinsic transcriptional activity of this transcriptional factor, implying a special significance for CSN5 controlled p53 in human cellular response to curcumin.

27626169

➶

reach

In addition, curcumin did not inhibit tumor growth of CSN5 knockout 4T1 cells in mice (XREF_FIG), suggesting that curcumin mediated tumor growth inhibition may be attributed primarily to CSN5 dependent regulation.

27866850

➶

reach

CSN5 associated kinase activity could be inhibited by curcumin, the treatment with which in mice bearing 4T1 tumors slowed tumor growth, increased tumor free survival, and increased IFNgamma+ CD8+ T cells when combined with CTLA-4 blockade.

30197875

➶

reach

We show that curcumin, an important inhibitor of CSN associated kinases, can downregulate not only CSN5 but also MDM2, which results in p53 stabilization.

17879958

➶

reach

Of note, curcumin, but not many other anticancer drugs, induces p53 predominantly by promoting CSN5 degradation [XREF_BIBR, XREF_BIBR].

27626169

Curcumin activates COPS5.

| 1

Curcumin activates COPS5. 1 / 1

| 1

➶

reach

Of note, CSN5 initiated cellular autophagy by curcumin treatment was abolished in p53-null HCT116p 53-/- cancer cells, which could be rescued by reconstitution with wild-type p53 or transcription inactive p53 mutant p53 R273H.

27626169

COPS5 affects proteolysis

| 9

COPS5 inhibits proteolysis.

| 7

COPS5 inhibits proteolysis. 7 / 7

| 7

➶

reach

Jab1 mediates protein degradation of the Rad9-Rad1-Hus1 checkpoint complex.

17583730

➶

reach

Silencing RNA knockdown or overexpression of CSN5 revealed that CSN5 promotes SIAH-1 expression, while CSN5 knockdown also attenuated SIAH-1 protein degradation.

24882689

➶

reach

Jab1 and CSN5 over-expression accelerated the protein degradation of Rad1 and Hus1 significantly, but had a weaker effect on Rad9 and (b)).

17583730

➶

reach

Overexpression of Jab1 accelerated the protein degradation of BRSK2 significantly.

22609399

➶

reach

However, when COPS5 is amplified and overexpressed in endocrine resistant cancer cells, elevated COPS5 and COP9 activity induces global NCoR protein degradation.

27375289

➶

reach

Inversely, overexpression of CSN5 by a Flag-CSN5 fusion construct led to accelerated SIAH-1 protein degradation.

24882689

➶

reach

Therefore, unbalanced activity of Jab1 and CSN5 can directly or indirectly block ubiquitin dependent proteolysis [XREF_BIBR].

17640378

COPS5 activates proteolysis.

| 2

COPS5 activates proteolysis. 2 / 2

| 2

➶

reach

Loss of a CSN subunit, especially CSN5 and CsnE with its catalytic deneddylase activity, leads to mis regulation of CRLs and to a disturbed protein degradation.

25142695

➶

reach

Moreover, the paramyosin accumulations of unc-96 and unc-98 mutants contain CSN-5, a highly conserved component of the COP9 signalosome, which is implicated in regulating ubiquitin mediated proteolysis and is located at A-bands.

27009202

COPS5 affects DNA Damage

| 9

COPS5 activates DNA Damage.

| 6

COPS5 activates DNA Damage. 6 / 6

| 6

➶

reach

These results indicate that Jab1 deficiency enhances DNA damage and decreases DNA repair after exposure to DNA damage stimuli.

22797071

➶

reach

22797071

➶

reach

On one hand, Cops5 suppresses the autophagic degradation of Mtch2 to direct cellular metabolism toward glycolysis and minimize reactive oxygen species (ROS) production, thereby reducing endogenous DNA damage.

31964807

➶

reach

By building on these findings, we found that Jab1 and CSN5 sensitized mouse embryonic fibroblasts to gamma radiation induced apoptosis and increased spontaneous DNA damage that could be attributed to reduced levels of the DNA repair protein Rad51 and increased levels of p53 [XREF_BIBR].

20955608

➶

reach

These results indicated that Jab1 and CSN5 deficiency enhances DNA damage and decreases DNA repair in NPC cells after exposure to DNA damaging stimuli.

22867945

➶

reach

Similarly, the levels of phospho- Chk2, a key molecule in the transduction of DNA damage signals [XREF_BIBR], increased in NPC cells after DNA damage exposure regardless of whether the cells were treated with Jab1 and CSN5 siRNA (although the phospho-Chk2 levels were higher in Jab1 and CSN5 deficient cells).

22867945

COPS5 inhibits DNA Damage.

| 3

COPS5 inhibits DNA Damage. 3 / 3

| 3

➶

reach

Previous investigation by our group showed that Jab1 deletion sensitized both primary embryonic fibroblasts and osteosarcoma cells to gamma-radiation-induced apoptosis and increased spontaneous DNA damage and homologous recombination defects 43.

27157611

➶

reach

Thus, in our next experiments we determined whether loss of Jab1 promotes apoptosis of NPC cells in response to DNA damage.

22797071

➶

reach

Loss of Jab1 sensitized cells to gamma radiation induced apoptosis and increased spontaneous DNA damage and homologous recombination defects.

22797071

COPS5 affects BRSK2

| 9

COPS5 inhibits BRSK2.

| 7

COPS5 inhibits BRSK2. 7 / 7

| 7

➶

reach

Overexpression of Jab1 accelerated the protein degradation of BRSK2 significantly.

22609399

➶

reach

Moreover, exogenous Jab1 reversed BRSK2 mediated G2/M arrest, indicating that BRSK2 is involved in the regulation of cell cycle in mammalian cells.

22609399

➶

reach

The results suggest that Jab1 is able to reverse BRSK2 mediated G2/M phase arrest in mammalian cells.BRSK2 shares high sequence homology with two mice SAD kinases.

22609399

➶

reach

Importantly, treatment with proteasome inhibitor MG132 rescued BRSK2 reduction mediated by Jab1, suggesting that Jab1 induced BRSK2 degradation through proteosome pathway.

22609399

➶

reach

Therefore, it will be meaningful to find out whether Jab1 mediated BRSK2 degradation is associated with oncogenic processes.In conclusion, we present novel findings showing that BRSK2 directly interac[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

22609399

➶

reach

In an attempt to test whether Jab1 mediates the degradation of BRSK2, we expressed the increasing doses of Jab1 in PANC-1 cells and examined endogenous BRSK2 protein level.

22609399

➶

reach

However, co-expression of Myc-Jab1 decreased HA-BRSK2 immunofluorescent signal and they co-localized in cytoplasm.

22609399

COPS5 decreases the amount of BRSK2.

| 2

COPS5 decreases the amount of BRSK2. 2 / 2

| 2

➶

reach

Silencing of Jab1 increased BRSK2 protein level in both HEK293T and PANC-1 cells.

22609399

➶

reach

Silencing of endogenous Jab1 increased the cellular BRSK2 protein level.

22609399

COPS5 affects Cyclin_E

| 9

COPS5 activates Cyclin_E.

| 5

COPS5 activates Cyclin_E. 4 / 4

| 4

➶

reach

For example, Doronkin et al. demonstrated that depletion of Jab1 and COPS5 induced cyclin E stability whereas Jab1 and COPS5 overexpression rapidly degraded cyclin E.

29535627

➶

reach

Our results show that the CSN regulates the turnover of Cyclin E. Decreased expression of CSN5 increased Cyclin E stability, and increased CSN5 expression stimulated rapid Cyclin E degradation.

12737805

➶

reach

Also, authors reported that decreased Jab1 and CSN5 expression increased cyclin E stability and that increased Jab1 and CSN5 expression stimulated rapid cyclin E degradation [XREF_BIBR].

22867945

➶

reach

We conclude that CSN5 stimulates Cyclin E degradation.We also overexpressed Cyclin E in wild-type flies to determine its effects on oogenesis when the CSN was not mutant.

12737805

Mutated COPS5 activates Cyclin_E. 1 / 1

| 1

➶

reach

This fact is not surprising because in CSN5 mutants, we found an accumulation of neddylated Cullin1, and a modest reduction in Nedd8 expression in double heterozygotes would be expected to suppress th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

12737805

COPS5 inhibits Cyclin_E.

| 4

COPS5 inhibits Cyclin_E. 4 / 4

| 4

➶

reach

We conclude that CSN5 stimulates Cyclin E degradation.We also overexpressed Cyclin E in wild-type flies to determine its effects on oogenesis when the CSN was not mutant.

12737805

➶

reach

These features offer a valuable model for studying the role of cell divisions in cellular differentiation and patterning in a defined lineage.In this paper, we report that CSN5 and CSN mediates SCF de[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

12737805

➶

reach

For example, Doronkin et al. demonstrated that depletion of Jab1 and COPS5 induced cyclin E stability whereas Jab1 and COPS5 overexpression rapidly degraded cyclin E.

29535627

➶

reach

Our results show that the CSN regulates the turnover of Cyclin E. Decreased expression of CSN5 increased Cyclin E stability, and increased CSN5 expression stimulated rapid Cyclin E degradation.

12737805

COPS5 affects SIAH1

| 9

COPS5 increases the amount of SIAH1.

| 5

COPS5 increases the amount of SIAH1. 5 / 5

| 5

➶

reach

In this study, we have observed that CSN5 effectively modulated SIAH-1 levels by different mechanisms.

24882689

➶

reach

Silencing RNA knockdown or overexpression of CSN5 revealed that CSN5 promotes SIAH-1 expression, while CSN5 knockdown also attenuated SIAH-1 protein degradation.

24882689

➶

reach

27640199

➶

reach

The data in Fig. 4 suggested that CSN5 would enhance SIAH-1 expression.

24882689

➶

reach

This is counter-intuitive at first sight, as it suggested that CSN5 both promotes SIAH-1 expression and degradation.

24882689

COPS5 inhibits SIAH1.

| 2

COPS5 inhibits SIAH1. 2 / 2

| 2

➶

reach

Silencing RNA knockdown or overexpression of CSN5 revealed that CSN5 promotes SIAH-1 expression, while CSN5 knockdown also attenuated SIAH-1 protein degradation.

24882689

➶

reach

Lastly, we demonstrate that CSN5 promotes SIAH-1 degradation in HCT116 and SW480 cells and that this is associated with its deNEDDylase activity.

24882689

COPS5 decreases the amount of SIAH1.

| 1

COPS5 decreases the amount of SIAH1. 1 / 1

| 1

➶

reach

27640199

COPS5 activates SIAH1.

| 1

COPS5 activates SIAH1. 1 / 1

| 1

➶

reach

Jab1 promotes glioma cell proliferation by regulating Siah1 and beta-catenin pathway.

27640199

COPS5 affects STAT3

| 9

COPS5 increases the amount of STAT3.

| 5

COPS5 increases the amount of STAT3. 3 / 3

| 3

➶

reach

Because Stat3 expression in NPC was associated with Jab1 expression, we sought to determine whether the overexpression of Stat3 could enhance Jab1 transcription in NPC cells.

27524414

➶

reach

In order to delineate whether Stat3 regulates Jab1 transcription, we performed a luciferase reporter assay with 5 ' deletion analysis of the human Jab1 promoter.

27524414

➶

reach

JAB1 knockdown decreased unphosphorylated STAT3 DNA binding activity, but tends to increase nuclear STAT3 expression level.

23911788

COPS5 increases the amount of modified STAT3. 2 / 2

| 2

➶

reach

Because Stat3 expression in NPC was associated with Jab1 expression, we sought to determine whether the overexpression of Stat3 could enhance Jab1 transcription in NPC cells.

27524414

➶

reach

As Jab1 expression in normal mammary epithelial cells is low, we asked whether overexpression of Stat3 could enhance Jab1 transcription in these cells.

21689417

COPS5 decreases the amount of STAT3.

| 2

COPS5 decreases the amount of STAT3. 2 / 2

| 2

➶

reach

Although JAB1 knockdown tended to increase nuclear STAT3 expression, it significantly decreased unphosphorylated STAT3 DNA binding activity.

| 8

➶

reach

Doxycycline inhibits CSN5 activity in vitro.

26142707

➶

reach

In this in vitro system, doxycycline inhibited CSN5 catalyzed deneddylation with an IC 50 about 110 muM.

26142707

➶

reach

Thus, doxycycline selectively inhibits CSN5, instead of being a general inhibitor of the JAMM family, likely through a mechanism more than mere zinc chelation.

26142707

➶

reach

The fact that doxycycline inhibited CSN5 activity significantly in vitro only at relatively high drug concentrations (IC 50 : ~ 110 muM) thus raised the question whether the concentrations of doxycycline in the DLBCL cells under our experimental conditions were sufficient to inhibit CSN5 activity.

26142707

➶

reach

Collectively, the results support the idea that doxycycline inhibits CSN5 function in cultured DLBCL cells.

26142707

➶

reach

To investigate whether doxycycline indeed inhibits the activity of CSN5 in DLBCL cells, we examined the effect of doxycycline treatment on cullin neddylation.

26142707

➶

reach

Doxycycline accumulates in DLBCL cells and inhibits CSN5 function in these cells.

26142707

➶

reach

Doxycycline treatment resulted in an increase in the neddylated (slower migrating) forms of Cullin-1 and Cullin-2 in the DLBCL cells, indicating that doxycycline inhibits CSN5 activity in DLBCL cells.

26142707

COPS5 affects calcium(2+)

| 1 7

COPS5 inhibits calcium(2+). 8 / 8

| 1 7

➶

reach

16483597

➶

reach

In rat, CSN5 inhibits cardiac L-type Ca 2+ channel activity through protein protein interactions.

27621744

➶

reach

Inhibition of CSN5 expression by siRNA enhanced the L-type Ca 2+ currents.

16483597

➶

sparser

Thus, the possible mechanisms by which CSN5 inhibits L-type Ca channels might be through an inhibition of the expression of the α subunit at the cell surface membrane and/or a reduction of availabilit[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

16483597

➶

reach

Because endogenous CSN5 expressed in COS7 cells may interact with and regulate the expressed Ca 2+ channels, we next examined effects of the inhibition of endogenous CSN5 on the Ca 2+ currents.Inhibit[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

16483597

➶

reach

Thus, the possible mechanisms by which CSN5 inhibits L-type Ca 2+ channels might be through an inhibition of the expression of the alpha 1C subunit at the cell surface membrane and/or a reduction of a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

16483597

➶

reach

The result suggests that endogenous CSN5 expressed in COS7 cells interacts with recombinant cardiac L-type Ca 2+ channel and that the endogenous protein level of CSN5 in these cells is sufficient to i[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

16483597

➶

reach

These data indicate that inhibition of endogenous CSN5 in COS7 cells enhances the activity of recombinant L-type Ca 2+ channels.Inhibition of CSN5 expression had no effect on the kinetics of L-type Ca[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

16483597

COPS5 affects Radiation, Ionizing

| 8

COPS5 activates Radiation, Ionizing. 8 / 8

| 8

➶

reach

Our study revealed that Jab1 depletion contributes to increased UV and IR and cisplatin sensitivity by increasing DNA damage and suppressing DNA repair, which in turn, contributes to an increase in cisplatin-, IR-, and UV induced apoptosis.

22797071

➶

reach

22797071

➶

reach

Consistent with impaired HR function in Jab1 knockdown cells, we also found that Jab1 +/- MEFs, compared with wild-type MEFs, significantly increased cell death in response to death stimuli UV IR and gamma-IR (XREF_FIG).

20802511

➶

reach

By contrast, exogenous Jab1 expression enhanced the resistance of NPC cells to cisplatin, IR and UV radiation.

22797071

➶

reach

In comparison, the levels of expression of Ku70, known to be an important protein in the NHEJ DNA-repair pathway, and of phospho-Chk2, a key molecule in the transduction of DNA damage signaling induced by DSBs [XREF_BIBR, XREF_BIBR], were increased after IR exposure regardless of whether the cells were treated with Jab1 and CSN5 or control siRNA.

22867945

➶

reach

These observations suggested that Jab1 and CSN5 is a major contributor to the resistance of NPC to UV radiation, IR, and cisplatin.

22867945

➶

reach

22797071

➶

reach

On the basis of our previous findings, we hypothesized that Jab1 contributes to cisplatin, IR and UV resistance.

22797071

S100A7 affects COPS5

| 8

S100A7 activates COPS5. 7 / 7

| 7

➶

reach

Psoriasin (S100A7), a small calcium binding protein that is highly expressed in early breast cancer, enhances Jab1 and CSN5 activity and promotes tumorigenesis [XREF_BIBR, XREF_BIBR].

20955608

➶

reach

Moreover, Psoriasin (S100A7), a small calcium binding protein, enhances Jab1 and COPS5 activity as well as AP-1 activity, and promotes tumorigenesis.

29535627

➶

reach

Overexpression of psoriasin increases nuclear Jab1 and CSN5 activity, resulting in increased AP-1 activity and reduced p27 expression [XREF_BIBR].

20955608

➶

reach

The over expression of psoriasin in MDA-MB-231 breast cancer cells was shown to increase nuclear Jab1 activity and enhance tumorigenesis in vivo in nude mice [XREF_BIBR].

17986321

➶

reach

Mechanistically, S100A7 enhances survival of breast cancer cells by binding to c-Jun activation domain binding protein 1 (Jab1) and increasing activity of NF-kappaB and p-Akt [XREF_BIBR].

28212564

➶

reach

The interaction of S100A7 with Jab1 appears to cause a cellular redistribution of Jab1, resulting in an accumulation in the nucleus [XREF_BIBR].

15217486

➶

reach

We previously observed that expression of S100A7 induces a relative increase in nuclear Jab1 in a breast cell line, and a concurrent reduction in p27 kip1 protein [XREF_BIBR].

15217497

S100A7 bound to JUN activates COPS5. 1 / 1

| 1

➶

reach

Psoriasin interacts with Jun activating binding protein 1 (Jab1), which is involved in multiple signal transduction pathways, including the regulation of c-Jun and AP1 transcription factors XREF_BIBR.

23300877

COPS5 affects cell differentiation

| 1 7

COPS5 activates cell differentiation.

| 1 5

COPS5 activates cell differentiation. 6 / 6

| 1 5

➶

reach

We found that increased expression of JAB1 promoted odontogenic differentiation of DPSCs via Wnt and beta-catenin signaling.

26989054

➶

reach

Interestingly, JAB1 activated CPNE1 related neuronal differentiation.

29448099

➶

sparser

Interestingly, JAB1 activated CPNE1 related neuronal differentiation.

29448099

➶

reach

Collectively, our findings suggest that JAB1 activates the neuronal differentiation ability of CPNE1 through the binding of C2A domain in CPNE1 with MPN domain in JAB1.

29448099

➶

reach

JAB1 accelerates odontogenic differentiation of dental pulp stem cells.

26989054

➶

reach

Moreover, the knockdown of Jab1 attenuated 5-HT 6 R agonist induced-Runx2 suppression as well as osteoblast differentiation as evidenced by ALP staining (XREF_FIG) and activity (F) and differentiation markers, ALP, OCN, and bone sialoprotein (BSP) (XREF_FIG).

27581523

COPS5 inhibits cell differentiation.

| 2

COPS5 inhibits cell differentiation. 2 / 2

| 2

➶

reach

In fact, Jab1 -/- nerves show reduced Schwann cell number and increased p27 levels, whereas genetic reduction of p27 in Jab1 -/- mice almost rescues Schwann cell number, differentiation, and the axonal sorting defect.

24344238

➶

reach

Dominant negatives of both JAB-1 and cytohesin-1 inhibited interleukin 2 production and impaired T helper type 1 differentiation.

14528303

COPS5 affects Neoplasm Invasiveness

| 8

COPS5 activates Neoplasm Invasiveness.

| 7

COPS5 activates Neoplasm Invasiveness. 7 / 7

| 7

➶

reach

CSN5 silencing inhibits invasion and arrests cell cycle progression in human colorectal cancer SW480 and LS174T cells in vitro.

26045788

➶

reach

Taken together, the results indicate that CSN5 can contribute to PC invasion and metastasis through activation of FOXM1 and MMP2 axis.

30352219

➶

reach

Strikingly, the knockdown of COPS5 significantly decreased both the migratory ability and invasiveness of both A549 and Panc-1 cell lines, in concert with the reduction of SNAIL and its downstream target protein, Vimentin [XREF_BIBR].

29755680

➶

reach

CSN5 promotes the invasion and metastasis of pancreatic cancer by stabilization of FOXM1.

30352219

➶

reach

Using an in vitro invasion assay, we found that knockdown of either Stat3 or Jab1 significantly decreased NPC cell invasion (XREF_FIG).

27524414

➶

reach

Further, silencing of CSN5 expression markedly inhibited PC invasion and metastasis in vitro and in vivo, accompanied by decreased MMP2 expression.

30352219

➶

reach

Overexpression of JAB1 promoted the proliferation, migration, and invasion of ESCC cells, and was significantly associated with poor prognosis of ESCC patients.

32064781

COPS5 inhibits Neoplasm Invasiveness.

| 1

COPS5 inhibits Neoplasm Invasiveness. 1 / 1

| 1

➶

reach

As shown in Figure XREF_FIG, their invasiveness were significantly suppressed by knocking-down of COPS5 in both H1650 and H2228 in concert with SNAIL reduction, suggesting the important role of COPS5 in the invasiveness of lung cancers independent of their specific oncogenic mutations.

29755680

COPS5 affects NEDD8

| 8

COPS5 inhibits NEDD8.

| 4

COPS5 inhibits NEDD8. 4 / 4

| 4

➶

reach

In particular, CSN inhibition of CRL4 DDB2 is non enzymatic, independent of CSN5 mediated cleavage of ubiquitin like protein Nedd8, whose conjugation to Cullins activates Cullin based ubiquitin ligase.

27696486

➶

reach

Indeed, conditional silencing of CSN5 in HEK293 cells increased the neddylation of cullins.

22655267

➶

reach

Constitutive photomorphogenesis 9 (COP9) signalosome 5 (CSN5), an isopeptidase that removes neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) moieties from cullins (thus termed " deNEDDylase ") and a subunit of the cullin RING E3 ligase regulating COP9 signalosome complex, attenuates proinflammatory NF-kappaB signaling.

28292897

➶

reach

CSN5 is responsible for the cleavage of NEDD8 from CRLs, and blocking deconjugation of NEDD8 traps the CRLs in a hyperactive state, thereby leading to auto-ubiquitination and ultimately degradation of the substrate recognition subunits.

27981705

COPS5 activates NEDD8.

| 4

COPS5 activates NEDD8. 4 / 4

| 4

➶

reach

Knockdown of the CSN subunit 5 (CSN5) and suppression of CSN mediated removal of Nedd8 (deneddylation) reduce FBP levels in human cells [10,11] indicating that a major function of the CSN is the prote[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

23328082

➶

reach

The Jab1 and MPN domain metalloenzyme (JAMM) motif in the Jab1 and Csn5 subunit was found to underlie CSN 's Nedd8 isopeptidase activity.

12183637

➶

reach

NEDD8 cleavage by CSN is catalysed by CSN5, a Zn (2+)-dependent isopeptidase that is inactive in isolation.

25043011

➶

reach

The Csn5 subunit in S. pombe and D. melanogaster underlies the Nedd8 isopeptidase activity of the CSN XREF_BIBR.

21151958

COPS5 affects MIF

| 8

COPS5 inhibits MIF.

| 5

COPS5 inhibits MIF. 5 / 5

| 5

➶

reach

This interaction appears indirect through CSN5 since depletion of CSN5 attenuated the association of exogenous HIF1alpha and MIF, placing CSN5 at the center of the tripartite interaction.

26352431

➶

reach

An indirect mechanism between Jab1 and COPS5 and PI3K and AKT pathway has been identified that Jab1 and COPS5 inhibits MIF (autocrine macrophage migration inhibitory factor) secretion and its autocrine pro survival activities and subsequently controls MIF mediated activation of PI3K and AKT signaling.

29535627

➶

reach

29535627

➶

reach

Lue et al. [XREF_BIBR] reported that CSN5 functions as a molecular link that retains MIF in the intracellular pools, indicating that CSN5 negatively regulates autocrine MIF activity.

26352431

➶

reach

It appears that a certain optimal cellular JAB1 concentration is needed to facilitate ERK activation by MIF, as a decrease in JAB1 levels, but also JAB1 overexpression, leads to impaired MIF stimulate[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

16122907

COPS5 activates MIF.

| 3

COPS5 activates MIF. 3 / 3

| 3

➶

reach

Bucala suggests that higher MIF concentrations, that are typically associated with some of the enzymatic activities of MIF and its direct stimulation of TNF and NO in macrophages, could be responsible[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

11932196

➶

reach

The sustained ERK activation induced by MIF was suggested to be mediated by autocrine MIF, and Rho GTPase, MLCK activation may be involved in this process XREF_BIBR, XREF_BIBR, while Jab1 inhibits the sustained ERK activation likely by blocking MIF secretion XREF_BIBR, XREF_BIBR.

21283538

➶

reach

Subsequent degradation may occur through JAB 's COP9 signalosome associated role in ubiquitin-E3 ligase-26 S proteasome mediated protein degradation.On the other hand, our siRNA experiments clearly in[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

16122907

COPS5 affects CTNNB1

| 8

COPS5 activates CTNNB1.

| 4

COPS5 activates CTNNB1. 4 / 4

| 4

➶

reach

Taken together, these findings suggest that Jab1 promotes glioma cell proliferation and increased expression of Jab1 in glioma patients may amplify beta-catenin signaling to contribute to glioma cell proliferation.

27640199

➶

reach

CSN5 knock-down led to reduced beta-catenin and phospho-bcatenin levels and this was paralleled by reduced CRC cell proliferation and reduced apoptosis rates, whereas the short-term beta-catenin protein stability was enhanced by CSN5 knock-down in SW480 cells.

22668871

➶

reach

Analysis of immunoblots revealed that beta-catenin was downregulated in recipient cells treated with CSN5 knockdown supernatants from donor cells.

28229932

➶

reach

Jab1 promotes glioma cell proliferation by regulating Siah1 and beta-catenin pathway.

27640199

COPS5 increases the amount of CTNNB1.

| 3

COPS5 increases the amount of CTNNB1. 3 / 3

| 3

➶

reach

Together, these experiments indicated that SIAH-1 promotes beta-catenin degradation in HCT116 cells.The data so far suggested that a CSN5 knockdown attenuates beta-catenin levels and Wnt and beta-cate[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

24882689

➶

reach

We have previously demonstrated that CSN5 knockdown leads to decreased beta-catenin levels in CRC cell lines, thereby diminishing WNT signaling activity [27,28].

28229932

➶

reach

We previously showed that CSN5 and JAB1 increases total beta-catenin levels while it also promotes the short-term proteasomal degradation of beta-catenin in SW480 CRC cells [30].

24882689

COPS5 inhibits CTNNB1.

| 1

COPS5 inhibits CTNNB1. 1 / 1

| 1

➶

reach

At the same time, we found that CSN5 also promotes the degradation of beta-catenin in SW480 cells, indicating that the effect of CSN5 on beta-catenin levels and associated Wnt signaling could be dicho[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

24882689

COPS5 affects HIF1A

3 | 5

COPS5 activates HIF1A.

2 | 3

COPS5 activates HIF1A. 3 / 3

| 3

➶

reach

Second, in a manner independent of the CSN holocomplex, CSN5 (or a CSN5 containing small complex) promotes cell proliferation by inducing p27 degradation [22,23] and HIF1-alpha stabilization [41].

18926707

➶

reach

While Jab1 promotes HIF-1alpha stability and transactivation, p53 degrades HIF-1a and decreases its transactivation.

29535627

➶

reach

However, in contrast to the studies involving MIF regulation of the SCF complex resulting in enhanced degradation and decreased stability of p27 and Cdc25A proteins, MIF and CSN5 regulates HIF-1alpha turnover resulting in enhanced stability and decreased degradation of HIF-1alpha.

19186177

COPS5 activates HIF1A. 2 / 2

2 |

➶

bel

Moreover, Jab1-enhanced transcriptional activity of HIF-1 under hypoxia led to increase the expression of VEGF, a major HIF-1 target gene. Furthermore, Jab1 increased HIF-1alpha protein levels, which was due to the enhanced HIF-1alpha stability

11707426

➶

bel

Jab1 acts as a cofactor to stimulate transcription of genes regulated by NFKB, AP1 and HIF1 transcription factors

15217486

COPS5 increases the amount of HIF1A.

1 | 1

COPS5 increases the amount of HIF1A. 2 / 2

1 | 1

| 1

➶

reach

Meanwhile, endogenous COPS5 levels were also gradually upregulated by overexpression of increased amounts of UCHL3.

28583475

UCHL3 decreases the amount of COPS5.

| 2

UCHL3 decreases the amount of COPS5. 2 / 2

| 2

➶

reach

Since COPS5 have been demonstrated to downregulate Cullin1 neddylation and activity, we speculate that UCHL3 could downregulate the activity of SCF beta and TrCP complex by upregulating cellular COPS5[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

28583475

➶

reach

We found that UCHL3 knockdown noticeably upregulated ubiquitination levels of COPS5.

28583475

UCHL3 activates COPS5.

| 1

UCHL3 activates COPS5. 1 / 1

| 1

➶

reach

The result showed that FH-UCHL3 overexpression obviously blocked protein degradation of COPS5, suggesting that UCHL3 enhances COPS5 protein stability.

28583475

RELA affects COPS5

| 2 5

RELA activates COPS5.

| 2 4

RELA activates COPS5. 6 / 6

| 2 4

➶

reach

In addition, p65 stimulated CSN5 activation, whereas a dominant negative IkappaBalpha mutant (IkappaBalpha 2SA) abolished p65 induced COPS5 promoter activation (XREF_FIG).

27866850

➶

reach

We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-kappaB p65, is required for TNF-alpha-mediated PD-L1 stabilization in cancer cells.

27866850

➶

reach

P65, but not its heterodimeric partner p50, stimulated CSN5 activation through the p65 binding site, and mutation of the binding site on the COPS5 promoter abrogated p65 mediated COPS5 promoter activity (XREF_FIG).

27866850

➶

sparser

Transcriptional Activation of CSN5 by p65 Is Required for TNF-α-Mediated PD-L1 Stabilization.

27866850

➶

sparser

Transcriptional Activation of CSN5 by p65 Is Required for TNF-α-Mediated PD-L1 Stabilization.

27866850

➶

reach

Transcriptional Activation of CSN5 by p65 Is Required for TNF-alpha-Mediated PD-L1 Stabilization.

27866850

RELA increases the amount of COPS5.

| 1

RELA increases the amount of COPS5. 1 / 1

| 1

➶

reach

Together with the positive correlation between p65 and CSN5 found in the Cancer Cell Line Encyclopedia (XREF_SUPPLEMENTARY), these results suggested that TNF-alpha-activated p65 transcriptionally upregulates CSN5 expression, which is required for TNF-alpha-mediated PD-L1 stabilization and related functions.

27866850

COPS5 affects cell growth

| 1 6

COPS5 activates cell growth.

| 5

COPS5 activates cell growth. 5 / 5

| 5

➶

reach

Experiments showing that the knock-down of p8 expression results in a strong inhibition of Jab1 activity confirmed that the mechanism by which Jab1 promotes cell growth by decreasing p27 level is p8 dependent.

16300740

➶

reach

27157611

➶

reach

Jab1 and CSN5 promotes NPC cell growth.

22867945

➶

reach

We also found that knockdown of CSN5 remarkably suppressed cell growth by inducing cell cycle arrest and apoptosis promotion in NSCLC cells.

29596838

➶

reach

XREF_BIBR used T83 (a new 4-arylidene curcumin analogue) to inhibit the expression of Jab1 in NPC cells, demonstrating that inhibition of Jab1 could reduce tumor cell growth, induce G 2 / M arrest, and increase tumor cell apoptosis, thus enhancing the sensitivities of NPC cells to radiotherapy.

25859408

COPS5 inhibits cell growth.

| 1 1

COPS5 inhibits cell growth. 2 / 2

| 1 1

➶

reach

21127074

➶

sparser

Furthermore, restoration of p57 levels induced by loss of Jab1 inhibited tumor cell growth and further increased cell apoptosis in HCC cells.

26606000

COPS5 affects cell death

| 7

COPS5 inhibits cell death.

| 4

COPS5 inhibits cell death. 4 / 4

| 4

➶

reach

20802511

➶

reach

However, the molecular mechanisms by which loss of JAB1 leads to cell death are still unclear.

20802511

➶

reach

Deletion of both Jab1 alleles caused embryonic lethality and accelerated cell death in blastocysts, indicating the essential role of Jab1 during mouse development.

20802511

➶

reach

CSN5 knockdown caused mitotic defects, G2/M arrest and apoptotic cell death.

19400951

COPS5 activates cell death.

| 3

COPS5 activates cell death. 3 / 3

| 3

➶

reach

20802511

➶

reach

Interestingly, siRNA mediated depletion of Jab1 inhibited cell proliferation and accelerated apoptotic cell death in NPC.

22350412

➶

reach

In both, Bezielle inhibited cell proliferation, induced cell death and G2 cycle arrest by regulating the mediator proteins Jab1, p27 (Kip1) and p21 (Cip1).

21509784

COPS5 affects Cell Survival

| 7

COPS5 activates Cell Survival.

| 5

COPS5 activates Cell Survival. 5 / 5

| 5

➶

reach

Jab1 mediated cell viability changes after UV and treatment with HU is tightly correlated with the lowered level of the 9-1-1 complex in cells).

17583730

➶

reach

Knock-down of Csn5 and JAB1 clearly enhanced basal NF-kappaB activity and improved cell survival under stress.

19656241

➶

reach

Finally, we demonstrate that a novel, highly specific small molecule inhibitor of JAB1, CSN5i-3, reduces osteosarcoma cell viability, and has specific effects on the ubiquitin-proteasome system in OS.

32390003

➶

reach

The deletion of Jab1 in limb bud OPCs impairs cell survival and inhibits chondrogenesis, consequently leading to a severe limb shortening phenotype in Jab1 cKO mice.

24604556

➶

reach

These results suggest that overexpression of CSN5 may contribute to both cell survival and proliferation and thus represent a prognostic marker for malignant conversion in liver cancer.

21499307

COPS5 inhibits Cell Survival.

| 2

COPS5 inhibits Cell Survival. 2 / 2

| 2

➶

reach

This data indicated that Jab1 inactivation significantly impaired the cell survival in the presence of DNA damage, which is consistent with our interpretation that defects in DNA repair occurred in the Jab1-knockdown cells.

20802511

➶

reach

To examine the potential consequence of Jab1 suppressed DNA synthesis recovery from blockage, we tested whether Jab1 over-expression could also reduce cell viability after treatment with replication b[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

17583730

COPS5 affects SOX9

| 7

COPS5 activates SOX9.

| 4

COPS5 activates SOX9. 4 / 4

| 4

➶

reach

Moreover, in Jab1 knockout mutants, Sox9 expression and activity was severely compromised, suggesting Jab1 positively regulates Sox9 in early growth plate development.

27418125

➶

reach

Notably, Jab1 by itself did not activate Sox9 reporter in 10T1/2 cells (XREF_FIG).

24604556

➶

| 2 1

COPS5 inhibits CDKN2A. 3 / 3

| 2 1

➶

reach

Ubiquitination assay was performed to validate whether ubiquitination is involved in Jab1 mediated p14ARF degradation.

32458234

➶

eidos

Furthermore , Jab1 decreased the expression of p14ARF though ubiquitination independent proteasomal degradation .

32458234

➶

eidos

Then , we investigated the mechanism that how Jab1 induced p14ARF depletion .

32458234

COPS5 decreases the amount of CDKN2A.

| 1 2

COPS5 decreases the amount of CDKN2A. 3 / 3

| 1 2

➶

trips

Jab1 promotes gastric cancer tumorigenesis via non-ubiquitin proteasomal degradation of p14ARF.

32458234

➶

reach

Expression of the tumor suppressor p16 (INK4a) was inversely correlated with that of JAB1, and the oncoprotein SMYD3, a newly identified JAB1 interactor, suppressed transcription of p16 in cooperation with JAB1.

18667426

➶

reach

Furthermore, Jab1 decreased the expression of p14ARF though ubiquitination independent proteasomal degradation.

32458234

COPS5 activates CDKN2A.

| 1

COPS5 activates CDKN2A. 1 / 1

| 1

➶

reach

Then, we investigated the mechanism that how Jab1 induced p14ARF depletion.

32458234

COPS5 affects Ubiquitin

| 1 6

COPS5 inhibits Ubiquitin.

| 1 3

COPS5 inhibits Ubiquitin. 3 / 3

| 1 2

➶

reach

While Csn5 is thought to impede the action of ubiquitin ligases through shaving cullins from their Rub1 and Nedd8 modification (and possibly also by deubiquitinating substrates bound to the cullins), the outcome of Rpn11 inhibition will depend largely on whether Rpn11 participates primarily in shaving substrates from their chains, promoting release and rescue, or in trimming the polyubiquitin tag, allowing for proteolysis quality control (XREF_FIG).

14737189

➶

eidos

Indeed , ectopic expression of IFIT3 in U937 human myeloid cells resulted in the sequestration of JUN activation domain-binding protein 1 ( JAB1 ; also known as COPS5 ) , which limited ubiquitin - and proteasome-dependent degradation of cyclin-dependent kinase inhibitor 1B ( also known as p27 and KIP1 ) .

23237964

➶

reach

Mechanistic studies showed that Jab1 induced ubiquitin independent proteasomal p14ARF degradation in gastric cancer cells.

32458234

COPS5 bound to MIF inhibits Ubiquitin. 1 / 1

| 1

➶

reach

Hence, MIF interacts with Jab1 and CSN5 and negatively regulates the cullin-1-containing ubiquitin E3 ligase complex with effects on p27- and E2F1-3-dependent cell cycle control [XREF_BIBR, XREF_BIBR].

22973314

COPS5 activates Ubiquitin.

| 2

COPS5 activates Ubiquitin. 2 / 2

| 2

➶

reach

| 2

COPS5 activates MYC. 2 / 2

| 2

➶

reach

However, a protein called CSN5 (also known as Jab1) that had been previously shown to posttranscriptionally promote MYC activation in breast epithelium [XREF_BIBR] was found to be overexpressed in early HCC in parallel with induction of the MYC regulated gene expression signature.

21559202

➶

reach

23911788

COPS5 decreases the amount of MYC.

| 2

COPS5 decreases the amount of MYC. 1 / 1

| 1

➶

reach

20802511

COPS5 decreases the amount of MYC. 1 / 1

| 1

➶

reach

Moreover, knockdown of CSN2 or CSN5 did not upregulate c-Myc protein expression in NIH3T3 cells (Figs.

24457827

COPS5 inhibits MYC.

| 1

COPS5 inhibits MYC. 1 / 1

| 1

➶

reach

In contrast, CSN5 knockdown led to accumulation of the neddylated form of Cullin-1 and destabilization of Fbxw7, causing accumulation of Myc (XREF_FIG).

25395170

COPS5 affects localization

| 6

COPS5 activates localization.

| 5

COPS5 activates localization. 5 / 5

| 5

➶

reach

Jab1 and CSN5 induces the cytoplasmic localization and degradation of RUNX3.

19350572

➶

reach

Jab1 induces the cytoplasmic localization and degradation of p53 in coordination with Hdm2.

16624822

➶

reach

Jun activation domain binding protein 1 (Jab and CSN5) induces the cytoplasmic localization and degradation of RUNX3 [XREF_BIBR].

21268057

➶

reach

Jab1 mediates cytoplasmic localization and degradation of West Nile virus capsid protein.

16882664

➶

reach

JAB1 induces p53 cytoplasmic localization and its subsequent degradation, which helps to maintain low levels of p53 under normal conditions XREF_BIBR, XREF_BIBR, XREF_BIBR.

24870804

COPS5 inhibits localization.

| 1

COPS5 inhibits localization. 1 / 1

| 1

➶

reach

Jab1 functionally inactivates several key negative regulatory proteins by affecting their subcellular localization, degradation, phosphorylation, and deneddylation, thereby acting as a positive regulator of cellular proliferation.

21689417

TNF affects COPS5

| 6

TNF increases the amount of COPS5.

| 4

TNF increases the amount of COPS5. 4 / 4

| 4

➶

reach

TNF-alpha Upregulates CSN5 Expression to Stabilize PD-L1.

27866850

➶

reach

Among the 52 deubiquitinating enzymes identified, CSN5, which possesses enzyme activity in the COP9 signalosome, was robustly expressed in response to TNF-alpha treatment in three cell lines examined (XREF_FIG).

27866850

➶

reach

The results suggested that TNF-alpha upregulates expression of CSN5, which interacts and deubiquitinates PD-L1 for protein stabilization.

| 5

➶

reach

23127558

➶

reach

CSN5 and Jab1 elimination inhibited progression of the cell cycle at multiple points, seemed to initiate p53 independent senescence and increased the ploidy of cells.

20974137

➶

reach

Further studies revealed that depletion of Jab1 inhibited cell proliferation, and induced premature senescence characterized by upregulation of senescence associated- beta-galactosidase activity and increased expression of CDK inhibitors.

29535627

➶

reach

It will be promising to explore small molecules which inhibit interaction between Jab1 and CDK2 but do n't affect the deneddylase activity of Jab1, which may induce senescence without affecting global proliferation and the cell cycle, resulting in the development of anti-cancer drugs with minimum side effects.

29535627

➶

reach

Depletion of CSN5 induces senescence in p53-null fibroblasts XREF_BIBR, but knockout of the CSN5 gene upregulates p53 expression XREF_BIBR, indicating that CSN5 occurs upstream of both p53 dependent and -independent senescence pathways (XREF_FIG) and that interaction between CSN5 and CDK2 may take part in the p53 independent pathway.

23316279

COPS5 affects CPNE1

| 5

COPS5 activates CPNE1. 5 / 5

| 5

➶

reach

Collectively, our findings suggest that JAB1 activates the neuronal differentiation ability of CPNE1 through the binding of C2A domain in CPNE1 with MPN domain in JAB1.

29448099

➶

reach

Interestingly, JAB1 activated CPNE1 related neuronal differentiation.

29448099

➶

reach

Defining the interaction modules on both proteins will be important to further characterize the mechanism of CPNE1 mediated cell differentiation by JAB1.

29448099

➶

reach

It is interesting point to find about detail mechanism of JAB1 up-regulation of CPNE1 function.Generally, the function of the MPN domain has been related to ubiquitin isopeptidase and deubiquitinase i[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

29448099

➶

reach

Nevertheless, it is not clear about the mechanism of JAB1 up-regulation of CPNE1 function.

29448099

COPS5 affects senp8

| 5

COPS5 inhibits senp8.

| 3

COPS5 inhibits senp8. 3 / 3

| 3

➶

| 4

COPS5 activates CUL. 4 / 4

| 4

➶

reach

Reconciling this paradox, we show here that Csn5 catalysed cullin (Cul) deneddylation and Ubp12 mediated deubiquitination cooperate in maintaining the stability of labile substrate adapters, thus facilitating CRL function.

15793566

➶

reach

In turn, the protected Jab1 activity can prevent the degradation of Cullin RING E3 ligases by the Ub/Ub like dependent degradation pathways.

32456285

➶

reach

These observations present a paradox : If CSN5 causes Cullin deneddylation via its metalloprotease activity, why does CSN promote CRL activity?

25395170

➶

reach

Thus, both a 2-hour MLN treatment and a long-term CSN5 siRNA knockdown attenuate the degradation of SIAH-1, while a 2-hour MLN treatment applied to CSN5 siRNA-knockdown cells does not further add to t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

24882689

COPS5 inhibits CUL.

| 1

COPS5 inhibits CUL. 1 / 1

| 1

➶

reach

Here, we examined whether repression of CSN5 expression (and thereby inhibition of CULLIN deneddylation) might influence ADORA2B dependent stabilization of PER2.

22504483

COPS5 affects CD274

| 5

COPS5 increases the amount of CD274.

| 3

COPS5 increases the amount of CD274. 3 / 3

| 3

➶

| 3

COPS5 activates ERN1. 2 / 2

| 2

➶

reach

Upon ER stress, JAB1 dissociates from IRE1alpha, allowing IRE1alpha to splice XBP1 mRNA into XBP1s, suggesting that JAB1 inhibits IRE1alpha through its binding 55.

28550308

➶

reach

Nevertheless, our data suggested the possibility that JAB1-IRE1alpha binding was increased to suppress UPR when the stimulus was weak, while JAB1 rapidly dissociated from IRE1alpha to allow IRE1alpha [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

15234121

COPS5 bound to ERN1 activates ERN1. 1 / 1

| 1

➶

reach

We found a decrease of activated XBP1 mRNA (the processed form) due to ER stress in cells expressing JAB1 mutants compared with cells expressing wild-type JAB1, which was similar to the inhibitory eff[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

15234121

COPS5 inhibits ERN1.

| 2

COPS5 inhibits ERN1. 2 / 2

| 2

➶

| 1

➶

reach

This raised a number of questions : Is it possible that overexpression of CSN5 and other CSN subunits, as it was found in the majority of CRC cases, suppresses DKK1 expression and secretion?

28229932

COPS5 inhibits DKK1.

| 2

COPS5 inhibits DKK1. 2 / 2

| 2

➶

reach

While knockdown of CSN5 increased DKK1 in the supernatant, CSN5 overexpression led to reduced DKK1 secretion.

28229932

➶

reach

CSN5 and JAB1 suppresses the WNT inhibitor DKK1 in colorectal cancer cells.

28229932

COPS5 affects APP

| 5

COPS5 inhibits APP.

| 2

COPS5 inhibits APP. 2 / 2

| 2

➶

| 4

➶

reach

In the case of Luman, this regulatory mechanism does not seem plausible, since JAB1 repression of Luman was also observed in the GAL4 reporter system, in which Luman was recruited to the artificial GA[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

23583719

➶

reach

We found that JAB1 could repress the activation potential of Luman and decrease its protein stability.The Matchmaker 3 yeast two-hybrid system and a pre-transformed adult human brain Matchmaker cDNA l[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

23583719

➶

3 |

SP1 decreases the amount of COPS5. 3 / 3

3 |

➶

biopax:msigdb

| 2

LPA activates COPS5. 2 / 2

| 2

➶

reach

LPA did not alter the expression level of CSN5 (XREF_FIG), but LPA increased CSN5 abundance in the nucleus (XREF_FIG), indicating that LPA promotes nuclear translocation of CSN5.

26352431

➶

reach

LPA enhanced the interaction of CSN5 with MIF or HIF1alpha.

26352431

COPS5 affects unc-98

| 4

COPS5 inhibits unc-98.

| 3

COPS5 inhibits unc-98. 3 / 3

| 3

➶

reach

Knockdown of csn-5 results in an increase in the level of UNC-98 protein and a slight reduction in the level of UNC-96 protein, suggesting that normally CSN-5 promotes the degradation of UNC-98 and stabilizes UNC-96.

22621901

➶

reach

In the double knockdown of csn-5 and -6, the levels of UNC-98 protein were increased and the levels of UNC-96 protein levels were slightly reduced, suggesting that CSN-5 promotes the degradation of UNC-98 and that CSN-5 stabilizes UNC-96.

19535455

➶

reach

20414365

COPS5 activates unc-98.

| 1

COPS5 activates unc-98. 1 / 1

| 1

➶

reach

RNAi knockdown of CSN-5 results in an increase in UNC-98 protein, suggesting that the function of CSN-5 is to promote the degradation of UNC-98.

23146617

COPS5 affects Proteasome

| 4

COPS5 activates Proteasome.

| 3

COPS5 activates Proteasome. 3 / 3

| 3

➶

reach

Indeed, ectopic expression of IFIT3 in U937 human myeloid cells resulted in the sequestration of JUN activation domain-binding protein 1 (JAB1; also known as COPS5), which limited ubiquitin- and proteasome-dependent degradation of cyclin-dependent kinase inhibitor 1B (also known as p27 and KIP1).

23237964

| 2

COPS5 activates DNA repair. 2 / 2

| 2

➶

reach

27524414

➶

reach

25607111

COPS5 affects CDKN

| 4

COPS5 activates CDKN.

| 3

COPS5 activates CDKN. 3 / 3

| 3

➶

reach

Jun activation domain binding protein 1 (Jab1) was originally identified as a coactivator of activator protein 1 (AP-1) transcription and was also shown to promote degradation of the cyclin dependent kinase inhibitor, p27Kip1.

15480426

➶

reach

| 1

➶

reach

COPS5 (Jab1) protein increases beta site processing of amyloid precursor protein and amyloid beta peptide generation by stabilizing RanBP9 protein levels.

23926111

COPS5 activates RANBP9.

| 1

COPS5 activates RANBP9. 1 / 1

| 1

➶

reach

Indeed RanBP9 protein half-life is increased by COPS5, a novel RanBP9 interacting protein that increases the stability of its interacting proteins most likely through an action on the ubiquitin-proteosome system.

24592211

COPS5 affects HTR6

| 4

COPS5 activates HTR6.

| 2

COPS5 activates HTR6. 2 / 2

| 2

➶

reach

| 2

COPS5 inhibits CRL. 2 / 2

| 2

➶

sparser

CSN is regulated by auto-inhibition, which is only released upon binding of NEDDylated CRL to ensure that CSN5 specifically inhibits the active NEDDylated CRLs [127] .

| 2

COPS5 inhibits AKT. 2 / 2

| 2

➶

reach

In addition, CSN5 silencing may induce activation PI3K and AKT signal regulated cell invasion.

| 2

➶

reach

Jab1 expression level was inversely linked to that of p27, and all five cases with only cytoplasmic but not nuclear staining of p27 overexpressed Jab1.

16175894

➶

reach

Knockdown of Jab1 resulted in a remarkable increase in p27 levels and inhibition of cell proliferation, indicating that Jab1 targets p27 for degradation, thereby controlling its stability.

22350412

CDKN1B inhibits COPS5.

reach

14502271

➶

sparser

JAB1 activates JUN N-terminal kinase (JNK) to phosphorylate JUN and so functions as a co-activator of activator protein 1 (AP1) -a transcription factor that is implicated in cell growth, transformation and cell death 54 .

14502271

COPS5 affects HAND2

| 3

COPS5 activates HAND2. 3 / 3

| 3

➶

reach

We show that JAB1 binds directly to the HLH domain of HAND2 and increases HAND2 transcription stimulating activity.

15139020

➶

reach

JAB1 enhances HAND2 transcriptional activity by regulating HAND2 DNA binding.

15139020

➶

reach

Our data indicate that JAB1 augments HAND2 transcriptional activity by enhancing HAND2 DNA binding.

15139020

COPS5 affects DNA repair protein

| 3

COPS5 activates DNA repair protein. 3 / 3

| 3

➶

reach

22797071

➶

reach

22797071

➶

reach

30244171

COPS5 affects CUL3

| 3

COPS5 inhibits CUL3. 3 / 3

| 3

➶

reach

Nevertheless, the csn5 null mutation did not rescue the reduced Cul3 neddylation caused by the lack of Int6 since Cul3 neddylation in the Int6 173-1 -csn5 null double homozygous larvae is very similar to that of the Int6 173-1 single mutant (XREF_FIG, compare lanes 5 and 6).

18493598

➶

reach

However, by the time the cells initiate this phase, the cytoplasmic CSN5 or Nedd8 proteins could be already used up, preventing the successful execution of the Cullin3 dependent program.

19855832

➶

reach

Western blot analysis demonstrated that Jab1 deletion increased the abundance of neddylated CUL3.

30301860

COPS5 affects BRR2

| 3

COPS5 activates BRR2. 3 / 3

| 3

➶

reach

The Jab1 and MPN domain of Prp8 increases the unwinding activity of Brr2 invitro.

23727230

➶

reach

It has been shown that the Jab1 and MPN domain enhances the unwinding activity of Brr2.

23727230

➶

reach

One possible mechanism how the Jab1 and MPN domain activates Brr2 could be releasing the brake imposed by the HLH domain.

23727230

Troglitazone affects COPS5

| 3

Troglitazone decreases the amount of COPS5.

| 2

Troglitazone decreases the amount of COPS5. 2 / 2

| 2

➶

| 2

PI3K inhibits COPS5. 2 / 2

| 2

➶

| 2

COPS5 inhibits RUNX2. 2 / 2

| 2

➶

| 2

COPS5 inhibits HUS1. 2 / 2

| 2

➶

| 2

COPS5 activates ERBB2. 2 / 2

| 2

➶

| 1

COPS5 bound to MIF inhibits E3_Ub_ligase. 1 / 1

| 1

➶

reach

22973314

COPS5 affects DDB2

| 3

COPS5 activates DDB2.

| 2

COPS5 activates DDB2. 2 / 2

| 2

➶

reach

The authors found that knockdown of the CSN5 component by the siRNA technique reduced the repair activity of the DDB2 complex and the RNA synthesis recovery activity of the CSA complex by about 50% in[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

12967661

➶

| 1

➶

reach

Further studies revealed that Jab1 promotes p57 's degradation through 26S proteasome pathway.

29535627

COPS5 decreases the amount of CORO1A.

| 1

Modified COPS5 decreases the amount of CORO1A. 1 / 1

| 1

➶

reach

Furthermore, restoration of p57 levels induced by loss of Jab1 inhibited tumor cell growth and further increased cell apoptosis in HCC cells.

26606000

COPS5 activates CORO1A.

24091666

➶

reach

24091666

COPS5 affects ABCB1

| 2

COPS5 increases the amount of ABCB1. 2 / 2

| 2

➶

reach

Subsequently, JAB1 knockdown significantly decreased the expression levels of MDR1, NANOG, and VEGF, which are STAT3 target genes.

23911788

➶

| 1

➶

reach

12737805

NEDD8 activates COPS5. 1 / 1

| 1

➶

reach

The presence of NEDD8 is required to activate the CSN5 active site.

CSN3 increases the amount of COPS5. 1 / 1

| 1

➶

reach

In this paper, the knockdown of CSN3 decreased the amount of CSN5 leading to an increase in nuclear NF-kappaB.

28623958

CSN3 decreases the amount of COPS5.

| 1

CSN3 decreases the amount of COPS5. 1 / 1

| 1

➶

| 1

COPS6 inhibits COPS5. 1 / 1

| 1

➶

reach

Notably, the MPN domain of CSN6 inhibited the association of CSN5 with Cullin-1, while the C-terminal domain had less impact (XREF_FIG).

25395170

COPS6 activates COPS5.

| 1

COPS6 activates COPS5. 1 / 1

| 1

➶

sparser

To gain additional insights into the molecular mechanism of CSN5 activation by CSN6, the crystal structure of the MPN − core fragment was determined by molecular replacement at 1.76 Å resolution, using the human Rpn8 ΔC orthologue as the search model (PDB code 2O95; xref ).

reach

27375289

COPS5 affects signal transduction

| 2

COPS5 bound to KMT2D activates signal transduction. 1 / 1

| 1

➶

reach

Intracellular human short form ALR (sfALR) binds to Jun Activation domain Binding protein 1 (JAB-1) and potentiates Activator Protein-1 (AP-1) signalling pathway in a sulfhydryl oxidase dependent manner XREF_BIBR.

22292055

COPS5 bound to JUN activates signal transduction. 1 / 1

| 1

➶

reach

27152307

COPS5 affects cell adhesion

| 2

COPS5 inhibits cell adhesion.

| 1

COPS5 inhibits cell adhesion. 1 / 1

| 1

➶

reach

28173800

COPS5 activates cell adhesion.

| 1

COPS5 activates cell adhesion. 1 / 1

| 1

➶

| 1

COPS5 inhibits WNT6. 1 / 1

| 1

➶

reach

Surprisingly, WNT6 was also downregulated by CSN5 overexpression as seen for the knockdown cells before.

28229932

COPS5 increases the amount of WNT6.

| 1

COPS5 increases the amount of WNT6. 1 / 1

| 1

➶

| 1

COPS5 inhibits NFKBIA. 1 / 1

| 1

➶

reach

As CSN5 is also known to promote the degradation of several proteins, e.g. p53, IkappaBalpha, or p27 [24,25,37], we asked if CSN5 might also affect the degradation of SIAH-1.

24882689

COPS5 activates NFKBIA.

| 1

COPS5 activates NFKBIA. 1 / 1

COPS5 inhibits KITLG. 1 / 1

11089976

COPS5 affects IL2

reach

Treatment of Csn5 depleted cells with the proteasome inhibitor MG132 largely restored normal levels of Fbx7, cyclin F, and Fbw7, whereas Skp2 levels were only partially rescued.

16401342

COPS5 activates FBXW7.

| 1

COPS5 activates FBXW7. 1 / 1

| 1

➶

| 1

➶

reach

These results suggest that an increase in degradation rate of ET A R after long-term ET-1 stimulation is mediated by an increase in the amount of Jab1 bound to ET A R.It is reported that in the absenc[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

20034471

COPS5 bound to MFSD11 activates EDN1. 1 / 1

| 1

| 1

CEBPB inhibits COPS5. 1 / 1

| 1

➶

reach

14 Other studies reported LIP mediated inhibition of the c-Jun coactivator Jab1, a novel candidate oncogene highly expressed in breast carcinoma.

28383550

CEBPB increases the amount of COPS5.

| 1

| 1

➶

reach

21935931

STAT1 affects COPS5

| 1

➶

biopax:msigdb

No evidence text available

RECK affects COPS5

| 1

RECK increases the amount of COPS5. 1 / 1

| 1

➶

reach

RECK inhibited the erbB signaling and attenuated the expression of the downstream molecules Jun activation domain binding protein 1 (JAB1) and the DNA repair protein RAD51 to impede DNA repair and to increase drug sensitivity.

26396917